Input:
Nuclear appearance of a factor that binds the CD28 response element within the interleukin-2 enhancer correlates with interleukin-2 production.
Activation of T lymphocytes requires the combined signaling of the T cell receptor and costimulatory molecules such as CD28. The ability of T cells to produce interleukin-2 (IL-2) is a critical control point in T lymphocyte activation. The IL-2 enhancer contains a functional motif named CD28 response element (CD28RE) that serves a role as a target for mitogenic T cell activation signals. The CD28RE sequence reveals similarity to the consensus kappaB binding motif. Here we demonstrate that CD28RE binds an inducible protein with a molecular mass of approximately 35 kDa called nuclear factor of mitogenic-activated T cells (NF-MATp35) that is clearly different from the known NF- kappaB/Rel family members. Induction of NF-MATp35 was shown to depend on de novo protein synthesis and was restricted to T cells that received a mitogenic combination of T cell stimuli, not necessarily including CD28 signaling. Nonmitogenic T cell stimulation did not result in appearance of NF-MATp35. These results indicate that mitogenic combinations of T cell activation signals are integrated at the level of NF-MATp35 induction. Similar to its effect on IL-2 production, cyclosporin A inhibited the induction of NF-MATp35. Taken together, these data demonstrate that the nuclear appearance of NF-MATp35 shows excellent correlation with IL-2 production, which is a unique characteristic among nuclear factors implicated in the control of IL-2 gene expression.

production

produce

production

production

expression

inhibited

production

control

expression

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Preassociation of STAT1 with STAT2 and STAT3 in separate signalling complexes prior to cytokine stimulation.
A variety of cytokines and growth factors act through an induction of gene expression mediated by a family of latent transcription factors called STAT (signal transducers and activators of transcription) proteins. Ligand-induced tyrosine phosphorylation of the STATs promotes their homodimer and heterodimer formation and subsequent nuclear translocation. We demonstrate here that STAT protein heterocomplexes exist prior to cytokine treatment. When unstimulated HeLa cells are ruptured in hypotonic buffer without salt or detergent, immunoadsorption of either STAT1 or STAT2 from the resulting cytosol yields coimmunoadsorption of the other STAT protein. Similarly, STAT1-STAT3 heterocomplexes are coimmunoadsorbed from hypotonic cytosol. STAT1 and STAT2 or STAT1 and STAT3 translated in reticulocyte lysate spontaneously form heterocomplexes when the translation lysates are mixed at 0 degrees C. Our data suggest that interferon-alpha /beta-induced tyrosine phosphorylation increases the stability of a preexisting, latent, STAT1-STAT2 signaling complex. Newly translated STAT1 binds in equilibrium fashion to STAT2 and STAT3, but we show that STAT2 and STAT3 exist in separate heterocomplexes with STAT1, consistent with a model in which STAT1 contains a common binding site for other STAT proteins.

tyrosine

yields coimmunoadsorption

yields coimmunoadsorption

heterocomplexes are coimmunoadsorbed

form heterocomplexes

form heterocomplexes

binds

binds

exist in separate heterocomplexes

exist in separate heterocomplexes

phosphorylation

tyrosine

phosphorylation

tyrosine

when

form heterocomplexes

induced

phosphorylation

increases the stability

induced

increases the stability

induced

separate

separate

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The word or phrase that expresses the event.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Inhibition of p105 processing by NF-kappaB proteins in transiently transfected cells.
Regulation of the transcription factor NF-kappaB involves proteasome-mediated processing of the NF-kappaB1 p105 precursor protein, which generates the p50 subunit of NF-kappaB. The processing of p105 occurs constitutively in vivo but can be markedly enhanced by various cellular activation agents, although the underlying regulatory mechanism is not yet clear. In the present study, we demonstrate that signal-mediated induction of p105 processing in human T cells is associated with de novo synthesis of this precursor protein. Transient transfection studies performed in COS7 cells revealed that the newly synthesized p105 protein appears to be more rapidly processed compared to its accumulated form that is already associated with the processed product p50. Interestingly, the processing rate of p105 is markedly inhibited in cells co-transfected with p50 or other NF-kappaB subunits, including RelA and c-Rel, that physically interact with p105. These findings suggest that the processing of p105 is subject to negative regulation by the various NF-kappaB subunits. We further demonstrate that p105 undergoes degradation in lipopolysaccharide-stimulated human monocytic cells. However, the inducible degradation of p105 is not coupled with the generation of p50. Together, these studies demonstrate that the processing and inducible degradation of p105 are differentially regulated.

RelA

c-Rel

associated

interact

interact

RelA

interact

c-Rel

generation

generates

undergoes

degradation

degradation

degradation

degradation

differentially regulated

degradation

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Globin gene switching. In vivo protein-DNA interactions of the human beta-globin locus in erythroid cells expressing the fetal or the adult globin gene program.
To characterize the protein-DNA interactions important for the developmental control of the human beta-globin locus, we analyzed by in vivo dimethyl sulfate footprinting erythroid cells expressing either the fetal or the adult globin developmental program. In the locus control region (LCR) of the beta-globin locus, in vivo footprints on NF-E2 (or AP-1) and GATA-1 motifs remained the same regardless of whether the fetal or the adult globin genes are expressed. In contrast, in vivo footprints on GT (CACCC) motifs differed between the cells expressing the fetal or the adult globin program. In promoter regions, the actively transcribed genes demonstrated extensive and consistent footprints over the canonical elements, such as CACCC and CCAAT motifs. The adult globin expressing cells displayed more extensive footprints than the fetal globin expressing cells in the 3' regulatory sequences of both the Agamma- and the beta-globin genes, suggesting a role of these 3' elements in beta-globin gene expression. Our results suggest that the bulk of protein-DNA interactions that underlies the developmental control of globin genes takes place in the gamma- and beta-globin gene promoters, and that GT motifs of the beta-globin locus LCR may play a role in the developmental regulation of human beta-globin gene expression, perhaps by increasing the probability of interaction of the LCR holocomplex with the fetal or the adult globin gene.

3' regulatory sequences

beta-globin

beta-globin

fetal

adult globin

beta-globin

fetal

adult globin genes

fetal

adult globin

Agamma-

beta-globin

beta-globin

gamma-

beta-globin

beta-globin

beta-globin

fetal

adult globin

interactions

beta-globin

footprints

3' regulatory sequences

Agamma-

footprints

3' regulatory sequences

beta-globin

interaction

fetal

interaction

adult globin

expressed

fetal

expressed

adult globin genes

expressing

fetal

expressing

adult globin

expression

beta-globin

expression

beta-globin

important

control

expressing

fetal

expressing

adult globin

more extensive

footprints

play a role

regulation

increasing

increasing

interaction

control

beta-globin

role

expression

regulation

expression

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Interleukin 10 induced c-fos expression in human B cells by activation of divergent protein kinases.
IL-10 is a potent mediator of human B cell growth and plasma cell formation. However, signal transduction of IL-10 in B cells is poorly understood. In this study the effect of IL-10 on the expression of the protooncogene c-fos was investigated, because Fos plays a potential role in the regulation of B cell proliferation and differentiation. B cells were purified from buffy coat preparations of healthy blood donors by positive selection using an anti CD20 monoclonal antibody and a MiniMACS separation unit. B cells were prestimulated with SAC for 48 hrs. Then, cells were incubated with medium or IL-10 (100 ng/ml) for 10 to 120 min. RNA was extracted by phenol/chloroform and c-fos expression was analyzed by PCR assisted mRNA assay. A significant 2-4 fold increase of c-fos expression was observed within 30 min of stimulation with IL-10 (p < 0.01). After 2 hrs c-fos expression declined to basal levels. The effect of IL-10 was dose-dependent with a maximum stimulation using 100 ng/ml of IL-10. The IL-10 effect on c-fos expression was not blocked by polymyxin B. Using the tyrosine kinase inhibitor genistein (10 microM) a complete inhibition of IL-10 induced c-fos expression was observed. In addition, H-7 (10 microM), a specific inhibitor of serine/threonine kinases, significantly blocked IL-10 mediated c-fos expression (p < 0.05). In conclusion, these data show that IL-10 induces c-fos expression in human B-cells by activation of tyrosine and serine/threonine kinases. Since this is the first report on IL-10 induced signal transduction, these data may help to identify the intracellular mechanisms by which IL-10 stimulates human B-cells.

Interleukin 10

c-fos

c-fos

c-fos

c-fos

c-fos

c-fos

c-fos

c-fos

c-fos

expression

c-fos

expression

c-fos

expression

c-fos

expression

c-fos

expression

c-fos

expression

c-fos

expression

c-fos

expression

c-fos

expression

c-fos

declined

expression

blocked

effect

inhibition

induced

blocked

mediated

induced

expression

increase

expression

induced

expression

mediated

expression

induces

expression

effect

expression

effect

expression

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
IL-10 inhibits nuclear factor-kappa B/Rel nuclear activity in CD3-stimulated human peripheral T lymphocytes.
IL-10 markedly reduces nuclear factor (NF)-kappa B/Rel nuclear activity induced in PBMC by stimulation with the anti-CD3 mAb OKT3. The inhibition is exerted specifically on the NF-kappa B/Rel activation induced by mAb OKT3, and not that produced by PMA. As judged by supershifting the DNA-protein complexes with Abs recognizing specific components of the NF-kappa B/Rel protein family, the p50/p65 (Rel A) heterodimeric form of NF-kappa B is primarily affected. The maximal effect is observed at the IL-10 concentration of 20 U/ml. IL-10 inhibitory activity is exerted on T lymphocytes and is mediated by monocytes. Indeed, monocytes pretreated with IL-10 are able so inhibit NF-kappa B nuclear activity in purified T lymphocytes stimulated with OKT3. Soluble factors do not appear to be involved in the mechanism of inhibition. On the other hand, the up-regulation of CD80 Ag, found on monocytes obtained from PBMC incubated with OKT3, is not detected after addition of IL-10, and the anti-CD28 mAb CLB-CD28/1 restores the NF-kappa B/Rel nuclear activity in IL-10-inhibited lymphocytes. Therefore, the NF-kappa B/Rel inhibition might be ascribed to a lack of cooperation between accessory cells and T lymphocytes, resulting from down-regulation of a costimulatory molecule, such as CD80, produced by IL-10 on activated monocytes. Our results demonstrate that IL-10 can inhibit the induction of NF-kappa B/Rel nuclear activity in CD3-stimulated T lymphocytes. Since inappropriate activation of kappa B-driven genes has a physiopathologic role in a number of diseases, such as HIV infection, our findings support the possibility of using this cytokine to suppress an undesirable activation of these transcription factors.

Rel A

CD80 Ag

affected

affected

down-regulation

up-regulation

CD80 Ag

detected

up-regulation

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Vitamin D3- and retinoic acid-induced monocytic differentiation: interactions between the endogenous vitamin D3 receptor, retinoic acid receptors, and retinoid X receptors in U-937 cells.
Retinoic acid (RA) and 1,25 alpha-dihydroxycholecalciferol (VitD3) are potent regulators of hematopoletic differentiation. Yet, little is known as to how the RA and VitD3 receptor network operates in hematopoietic cells, and whether receptor interactions can explain the interplay between the RA- and VitD3-signaling pathways during differentiation. Therefore, we analyzed the expression, DNA binding, and transcriptional activity of the endogenous RA and VitD3 receptors [retinoic acid receptors (RARs), retinoid X receptors (RXRs), and VitD3 receptor (VDR)] in the U-937 cell line, in which RA and VitD3 induce distinct monocytic differentiation pathways. VitD3 induction resulted in the formation of VDR/RXR DNA-binding complexes on both VitD3 response elements and RA response elements (RAREs). However, transcriptional activation was only observed from a VitD3 response element-driven reporter construct. Several DNA-binding complexes were detected on RAREs in undifferentiated cells. Stimulation by RA resulted in increased RAR beta/RXR DNA binding, activated RARE-dependent transcription, and increased expression of RAR-beta. Concomitant stimulation by VitD3 inhibited the RA-stimulated formation of RAR beta/RXR heterodimers, favoring VDR/RXR binding to the RARE. Also, VitD3 inhibited the expression of CD23 and CD49f, characteristic markers of retinoid-induced U-937 cell differentiation. In contrast, neither the RA-stimulated, RARE-mediated transcription nor the induced RAR-beta expression was suppressed by VitD3, suggesting that VitD3 selectively inhibited the retinoid-induced differentiation program but not the RARE-mediated signal. These results demonstrate a complex role for VitD3 in modifying the retinoid differentiation pathway and may have implications for differentiation-inducing therapy of hematopoietic tumors.

vitamin D3 receptor

VitD3 receptor

VDR

VDR

RAR beta

RAR-beta

RAR beta

VDR

RAR-beta

binding

VDR

formation

VDR

binding

RAR beta

heterodimers

RAR beta

binding

VDR

expression

VDR

expression

RAR-beta

expression

expression

expression

RAR-beta

inhibited

stimulated

inhibited

expression

suppressed

expression

resulted

formation

resulted in increased

binding

increased

expression

stimulated

heterodimers

favoring

expression

binding

induced

expression

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Calcium-dependent immediate-early gene induction in lymphocytes is negatively regulated by p21Ha-ras.
The induction of immediate-early (IE) response genes, such as egr-1, c-fos, and c-jun, occurs rapidly after the activation of T lymphocytes. The process of activation involves calcium mobilization, activation of protein kinase C (PKC), and phosphorylation of tyrosine kinases. p21(ras), a guanine nucleotide binding factor, mediates T-cell signal transduction through PKC-dependent and PKC-independent pathways. The involvement of p21(ras) in the regulation of calcium-dependent signals has been suggested through analysis of its role in the activation of NF-AT. We have investigated the inductions of the IE genes in response to calcium signals in Jurkat cells (in the presence of activated p21(ras)) and their correlated consequences. The expression of activated p21(ras) negatively regulated the induction of IE genes by calcium ionophore. This inhibition of calcium-activated IE gene induction was reversed by treatment with cyclosporin A, suggesting the involvement of calcineurin in this regulation. A later result of inhibition of this activation pathway by p21(ras) was down-regulation of the activity of the transcription factor AP-1 and subsequent coordinate reductions in IL-2 gene expression and protein production. These results suggest that p2l(ras) is an essential mediator in generating not only positive but also negative modulatory mechanisms controlling the competence of T cells in response to inductive stimulations.

c-fos

c-jun

reductions

gene expression

induction

induction

c-fos

induction

c-jun

occurs

induction

activated

expression of activated

gene expression

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Apoptosis signaling pathways in normal T cells: differential activity of Bcl-2 and IL-1beta-converting enzyme family protease inhibitors on glucocorticoid- and Fas-mediated cytotoxicity.
Fas-mediated apoptosis plays an important role in regulating the immune response in peripheral T cells. Restimulation of T cell blasts up-regulates Fas and Fas ligand expression, with subsequent interaction leading to cell death. Overexpression of Bcl-2 in tumor cells blocks apoptosis induced by many stimuli, but inhibition of Fas-mediated killing has not been consistently observed. To examine the behavior of Bcl-2 in normal cells, T cell blasts were transiently transfected with Bcl-2 and related gene products to determine the effect on apoptotic signaling. Transient overexpression of Bcl-2 in mouse and human T cell blasts did not block Fas-mediated apoptosis, whereas etoposide- and glucocorticoid-induced cytotoxicity was potently inhibited. Expression of Bcl-xL and adenovirus E1B 19K did not interfere with anti-Fas killing. In contrast, interleukin-1beta-converting enzyme family protease inhibitors Ac-DEVD-CHO and CrmA blocked Fas-mediated apoptosis. These results suggest that peripheral T cells use distinct apoptosis signaling pathways with differential sensitivity to Bcl-2 and interleukin-1beta-converting enzyme family protease inhibitors. Since T cells normally express Bcl-2 and Bcl-xL following activation, their inability to block Fas-mediated apoptosis may allow for the elimination of self-reactive cells and the appropriate regulation of immune responses.

Fas

Fas

Fas

Fas ligand

Fas

Fas

Bcl-xL

E1B 19K

Fas

Fas

Bcl-xL

Fas

interaction

Fas

Fas ligand

expression

Fas

expression

Fas ligand

Overexpression

transfected

overexpression

Expression

Bcl-xL

Expression

E1B 19K

express

express

Bcl-xL

up-regulates

expression

Overexpression

Overexpression

transfected

transfected

overexpression

overexpression

following

express

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Interferons induce normal and aberrant retinoic-acid receptors type alpha in acute promyelocytic leukemia cells: potentiation of the induction of retinoid-dependent differentiation markers.
Treatment of the acute promyelocytic (APL) cell line NB4 with interferon alpha (IFN(alpha)), as well as IFN(beta) and gamma, results in an increased expression of the transcripts coding for retinoic-acid receptor type alpha (RAR(alpha)) and the leukemia-specific retinoic acid receptor PML-RAR. Transcriptional induction of the RAR(alpha) and PML-RAR mRNAs is rapid and it is parallelled by an increase in the corresponding proteins. Up-regulation of RAR(alpha) and PML-RAR gene expression by IFN(alpha) is accompanied by a strong potentiation in the induction of 2 retinoid-dependent granulocytic markers, i.e., granulocyte-colony-stimulating factor receptor mRNA and leukocyte alkaline phosphatase. However, IFN(alpha) does not have any effects on the retinoid-dependent regulation of the myeloid surface markers CD11b and CD33. The IFN-dependent increase in RAR(alpha) levels and the enhancing effect of the cytokine on retinoid-dependent granulocytic markers expression may be a characteristic of PML-RAR positive cells, since the phenomena are not observed in HL-60 promyelocytes. Interferons as well as retinoids inhibit the growth of NB4 cells, although the 2 classes of compounds do not significantly interact in terms of anti-proliferative activity. These results suggest the possible use of combinations between IFNs and retinoic acid in the cyto-differentiating treatment of APL patients.

retinoic-acid receptors type alpha

retinoic-acid receptor type alpha

RAR(alpha)

leukemia-specific retinoic acid receptor

PML-RAR

RAR(alpha)

PML-RAR

RAR(alpha)

PML-RAR

granulocyte-colony-stimulating factor receptor

leukocyte alkaline phosphatase

RAR(alpha)

PML-RAR

expression

RAR(alpha)

expression

PML-RAR

levels

RAR(alpha)

induce

retinoic-acid receptors type alpha

results in an increased

expression

Transcriptional induction

RAR(alpha)

Transcriptional induction

PML-RAR

parallelled

Transcriptional induction

increase

increase

RAR(alpha)

increase

PML-RAR

Up-regulation

expression

induction

granulocyte-colony-stimulating factor receptor

induction

leukocyte alkaline phosphatase

dependent

granulocyte-colony-stimulating factor receptor

dependent

leukocyte alkaline phosphatase

increase

levels

observed

RAR(alpha)

effects

regulation

regulation

regulation

expression

RAR(alpha)

expression

PML-RAR

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
An IL-2 response element in the human IL-2 receptor alpha chain promoter is a composite element that binds Stat5, Elf-1, HMG-I(Y) and a GATA family protein.
Expression of the human interleukin-2 (IL-2) receptor alpha chain gene is potently upregulated by its own ligand, IL-2. In this study, we characterize an essential upstream IL-2 response element that contains both consensus and non-consensus GAS motifs, two putative Ets binding sites (EBS), one of which overlaps the consensus GAS motif, and a GATA motif, which overlaps the non-consensus GAS motif. We demonstrate that although the individual components of this element do not respond to IL-2, together they form a composite element capable of conferring IL-2 responsiveness to a heterologous promoter. Multiple factors including Stat5, Elf-1, HMG-I(Y) and GATA family proteins bind to the IL-2 response element and mutation of any one of these binding sites diminishes the activity of this element. An unidentified Ets family protein binds to the EBS overlapping the consensus GAS motif and appears to negatively regulate the human IL-2R alpha promoter. Thus, IL-2-induced IL-2R alpha promoter activity requires a complex upstream element, which appears to contain binding sites for both positive and negative regulatory factors.

promoter

promoter

IL-2 receptor alpha chain

HMG-I(Y)

interleukin-2 (IL-2) receptor alpha chain

HMG-I(Y)

IL-2R alpha

IL-2R alpha

binds

binds

binds

HMG-I(Y)

bind

bind

bind

HMG-I(Y)

Expression

interleukin-2 (IL-2) receptor alpha chain

negatively regulate

IL-2R alpha

promoter

upregulated

Expression

induced

IL-2R alpha

promoter

requires

induced

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Active suppression of the class II transactivator-encoding AIR-1 locus is responsible for the lack of major histocompatibility complex class II gene expression observed during differentiation from B cells to plasma cells.
In this study the genetic control of major histocompatibility complex (MHC) class II gene expression during the transition from B cell to plasma cell has been analyzed. Class II molecules are not expressed in plasma cells because of an active suppression resulting in the abrogation of class II gene transcription. We show here that the plasma cell-specific repressor function, designated SIR (suppressor of immune response genes), does not act directly on the transcription of class II genes, but instead on the transcription of the AIR-1 gene, whose product, the class II transactivator (CIITA), is fundamental for the regulation of the constitutive and inducible expression of MHC class II genes. This was unambiguously demonstrated by the fact that plasmacytoma x B cell hybrids carrying an AIR-1 locus derived from CIITA-expressing cells do not express CIITA-specific transcripts. Transfection of a cDNA containing the human CIITA coding sequence under the control of an heterologous promoter restores expression of human MHC class II genes in the hybrids and is responsible for de novo expression of mouse MHC class II genes in both the mouse plasmacytoma cell line and the hybrids. These results confirm and extend the notion of the functional conservation of the AIR-1 gene product across species barriers. Interestingly, in CIITA-transfected cell hybrids, cell surface expression of the human HLA-DQ heterodimer was not observed. This result was not attributable to lack of HLA-DQ alpha or -DQ beta transcription, because both transcripts were present in the CIITA-transfected hybrids, although at reduced levels. These findings further support our previous observations on the distinct regulation of expression of the human HLA-DQ class II subset, which may be thus controlled at the posttranscriptional level by a CIITA-independent mechanism.

class II transactivator

class II transactivator

CIITA

CIITA

CIITA

CIITA

CIITA

HLA-DQ alpha

-DQ beta

CIITA

CIITA

Transfection

CIITA

transfected

CIITA

present

HLA-DQ alpha

present

-DQ beta

transfected

CIITA

suppression

class II transactivator

act

transcription

lack

transcription

reduced levels

transcription

transfected

Active

suppression

express

transcripts

Transfection

under the control

transfected

transfected

transfected

transfected

under the control

Transfection

attributable

lack

transcription

CIITA

transcripts

CIITA

transcription

HLA-DQ alpha

transcription

-DQ beta

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Silencing of human fetal globin expression is impaired in the absence of the adult beta-globin gene activator protein EKLF.
Globin genes are subject to tissue-specific and developmental stage-specific regulation. A switch from human fetal (gamma)-to adult (beta)-globin expression occurs within erythroid precursor cells of the adult lineage. Previously we and others showed by targeted gene disruption that the zinc finger gene, erythroid Kruppel-like factor (EKLF), is required for expression of the beta-globin gene in mice, presumably through interaction with a high-affinity binding site in the proximal promoter. To examine the role of EKLF in the developmental regulation of the human gamma-globin gene we interbred EKLF heterozygotes (+/-) with mice harboring a human beta-globin yeast artificial chromosome transgene. We find that in the absence of EKLF, while human beta-globin expression is dramatically reduced, gamma-globin transcripts are elevated approximately 5-fold. Impaired silencing of gamma-globin expression identifies EKLF as the first transcription factor participating quantitatively in the gamma-globin to beta-globin switch. Our findings are compatible with a competitive model of switching in which EKLF mediates an adult stage-specific interaction between the beta-globin gene promoter and the locus control region that excludes the gamma-globin gene.

promoter

fetal globin

EKLF

human fetal (gamma)-

adult (beta)-globin

erythroid Kruppel-like factor

EKLF

beta-globin

EKLF

gamma-globin

EKLF

beta-globin

EKLF

beta-globin

gamma-globin

gamma-globin

EKLF

gamma-globin

beta-globin

EKLF

beta-globin

gamma-globin

interaction

EKLF

interaction

beta-globin

promoter

expression

fetal globin

expression

human fetal (gamma)-

expression

adult (beta)-globin

expression

beta-globin

expression

beta-globin

expression

gamma-globin

Silencing

expression

impaired

Silencing

absence

absence

EKLF

switch

expression

reduced

expression

Impaired

silencing

silencing

expression

switch

gamma-globin

excludes

mediates

gamma-globin

switch

expression

required

EKLF

expression

through

required

interaction

role

EKLF

regulation

elevated

gamma-globin

participating

EKLF

switch

switch

beta-globin

mediates

EKLF

interaction

regulation

gamma-globin

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Nasal NK- and T-cell lymphomas share the same type of Epstein-Barr virus latency as nasopharyngeal carcinoma and Hodgkin's disease.
Nasal T/NK-cell lymphomas can be further separated into those of natural killer (NK) cell lineage or of T-cell lineage, with differences in cellular phenotype, T-cell receptor (TcR) gene rearrangement and TcR transcript expression. Both NK- and T-cell subtypes are closely associated with Epstein-Barr virus (EBV). In this study, EBV gene expression was determined in 23 cases of nasal lymphoma (NL) by in situ hybridisation (ISH), reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry (IH). Of the 23 cases, 19 were classified as NK-cell and 4 as T-cell tumours. ISH for EBV-encoded small non-polyadenylated RNAs showed that all cases, whether NK or T, harboured EBV in virtually all tumour cells. RT-PCR demonstrated that NL of both subtypes expressed EBNAI of the QUK splice pattern, the latent membrane proteins, LMP1 and 2 and the BamHI A rightward transcripts in the absence of EBNA2 mRNAs, compatible with the latency type II pattern. In addition, analysis of EBV protein expression by IH revealed a heterogeneous pattern of EBV gene expression at the single-cell level consisting of both LMP1+ and LMP1- tumour cells, suggesting a mixture of latency I and II. Although 2 early lytic transcripts, BZLF1 and BHRF1, were also detected in 13 and 10 cases, respectively, the lack of ZEBRA staining in any case indicates that these lytic transcripts are most likely expressed by rare cells in the biopsies entering lytic cycle. The viral transcriptional pattern similar to that of nasopharyngeal carcinoma and Hodgkin's disease suggests that EBV can exploit common regulatory mechanisms for gene transcription in diverse host cell types. Down-regulation of immunogenic proteins (EBNA2-EBNA6) in nasal lymphoma may enable tumour cells to evade host cytotoxic T-cell surveillance.

EBNAI

ZEBRA

expressed

EBNAI

expressed

expressed

Down-regulation

Down-regulation

absence

detected

detected

lack

ZEBRA

expressed

expressed

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Identification and characterization of a leukocyte-specific component of the nuclear body.
The nuclear body (NB) is a cellular organelle that is involved in the pathogenesis of acute promyelocytic leukemia and viral infection. The NB is also a target of antibodies in the serum of patients with the autoimmune disease primary biliary cirrhosis. In this study, serum from a patient with primary biliary cirrhosis was used to identify a cDNA encoding a novel component of the NB, a 140-kDa protein designated Sp140. The predicted amino acid sequence of the amino-terminal portion of Sp140 was similar to Sp100, a previously identified NB protein. The carboxyl portion of Sp140 contained a zinc-finger domain and a bromodomain, motifs that are present in proteins regulating gene transcription. High levels of Sp140 mRNA were detected in human spleen and peripheral blood leukocytes, but not other human tissues. The level of SP140 mRNA in myeloid precursor cell lines HL60 and NB4 markedly increased in response to chemically induced cellular differentiation. Immunohistochemical techniques were used to demonstrate that SP140 localized to the NB in differentiated HL60 and NB4 cells. The location of Sp140 in the NB, and expression of this gene in cells involved in host defense, suggest that Sp140 may be involved in the pathogenesis of acute promyelocytic leukemia and viral infection.

NB

NB

expression

localized

NB

location

NB

High levels

detected

increased

level

detected

level

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Potent gene regulatory and antiproliferative activities of 20-methyl analogues of 1,25 dihydroxyvitamin D3.
The biological active form of vitamin D3, 1,25-dihydroxyvitamin D3 (VD), regulates cellular growth and differentiation. This provides the hormone with an interesting therapeutic potential. However, hypercalcemia is a side effect, which is caused by VD's classical action, the regulation of calcium homeostasis. This made the need for VD analogues with selectively increased cell regulatory properties. Studies with 20-epi analogues pointed out the importance of the carbon-20 position and led to the development of 20-methyl derivatives of VD. In this report the biological properties of the compounds ZK161422 and ZK157202, which are 20-methyl- and 20-methyl-23-eneanalogues, respectively, have been analyzed in comparison with VD. Both compounds show about 2-fold lower affinity to the VD receptor (VDR) than VD. However, compared to VD, their antiproliferative effect is up to 30-fold higher on human peripheral blood mononuclear cells and even up to 300-fold higher on human breast cancer MCF-7 cells. Whereas the hypercalcemic effect for ZK157202 is also increased 10-fold, ZK161422 has the same calcium-mobilizing potency as VD. Moreover, ZK161422, but not ZK157202, showed preference for gene activation from a promoter carrying a VD response element with a palindromic arrangement of two hexameric receptor binding sites spaced by 9 nucleotides (IP9) rather than for activation from a response element formed by a direct repeat spaced by 3 nucleotides (DR3). This observation supports a model, in which promoter selectivity reflects the selectively increased antiproliferative effect of VD analogues.

VD receptor

VDR

lower affinity

VDR

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Second messenger up-regulation of androgen receptor gene transcription is absent in androgen insensitive human prostatic carcinoma cell lines, PC-3 and DU-145.
A theoretical pathway of transcriptional regulation of the androgen receptor (AR) gene is via a cAMP response element (CRE) present in its promoter region (-508 to -501). After 20 h of stimulation with 8-bromo-cAMP, AR mRNA was upregulated in LNCaP but not in either PC-3 or DU-145 cell lines. We have demonstrated that the level of CRE binding protein (CREB) was the same in all cell lines and that the putative AR-CRE forms specific and compatible protein interactions with CREB. The ability to regulate AR gene transcription via the second messenger pathway is lost in the PC-3 and DU-145 cell lines. This may be an important primary mechanism of androgen insensitivity in prostate cancer.

androgen receptor

AR

AR

CRE binding protein

CREB

AR

CREB

AR

interactions

CREB

lost

regulate

via

transcriptional regulation

upregulated

AR

transcriptional regulation

AR

regulate

transcription

transcription

AR

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Activation of the NF-kappaB transcription factor in a T-lymphocytic cell line by hypochlorous acid.
Reactive oxygen species (ROS) such as hydrogen peroxide serve as second messengers in the induction of the transcription factor NF-kappaB, and hence in the activation and replication of human immunodeficiency virus type 1 (HIV-1) in human cells. During inflammatory reactions, many oxidative species are produced, one of which is hypochlorous acid (HOCl), which is responsible for the microbicidal effects of activated human polymorphonuclear leukocytes. Treatment of a T-lymphocytic cell line with micromolar concentrations of HOCl promoted the appearance of transcription factor NF-kappaB (the heterodimer p50/p65) in the nucleus of the cells, even in the absence of de novo protein synthesis. Western blot analysis of the NF-kappaB inhibitory subunits (IkappaB) demonstrated that both IkappaB-alpha proteolysis and p105 processing were induced by the treatment. NF-kappaB activation was very effective when cells were subjected to hyperthermia before being treated with HOCl. Various antioxidants, such as pyrrolidine dithiocarbamate, p-bromophenacyl-bromide and nordihydroguaiaretic acid could strongly reduce NF-kappaB translocation, demonstrating the importance of oxidative species in the transduction mechanism. Moreover, ACH-2 cells treated with HOCl or H2O2 released tumour necrosis factor-alpha (TNF-alpha) in the supernatants. The importance of TNF-alpha release in NF-kappaB induction by HOCl or H2O2 was demonstrated by the fact that: (1) the nuclear appearance of NF-kappaB was promoted in untreated cells; and (2) synergism between TNF-alpha and HOCl was detected. Collectively, these results suggest that HOCl should be considered as an oxidative species capable of inducing NF-kappaB in a T-lymphocytic cell line through a transduction mechanism involving ROS, and having a long-distance effect through subsequent TNF-alpha release.

nucleus

IkappaB-alpha

tumour necrosis factor-alpha

TNF-alpha

TNF-alpha

TNF-alpha

TNF-alpha

appearance

nucleus

appearance

nucleus

released

TNF-alpha

release

TNF-alpha

release

TNF-alpha

promoted

appearance

induced

proteolysis

treated with

released

subsequent

release

proteolysis

IkappaB-alpha

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Thymocytes control the CD4 gene differently from mature T lymphocytes.
We analyzed the activity of the enhancer, the promoter and the silencer of the human CD4 gene during T cell development using transgenic mice. Immunofluorescence studies on thymic populations of mice carrying transgenes in various combinations of these regulatory DNA elements revealed that thymocytes control the CD4 gene in a different manner than mature peripheral T lymphocytes. The 5'-positive regulatory unit, consisting of the promoter and the 5' enhancer, is already active at the CD4-CD8-double-negative (DN) stage of development. However, its activity becomes lower in the double-positive and a fraction of the CD4+ CD8int/- cell population, indicating that an additional enhancer, located in either the first or the third intron of the CD4 gene, is required for CD4 gene expression in this population. The other studied regulatory element is the minimal CD4 silencer which inhibits CD4 gene expression in peripheral CD8 T lymphocytes. This silencer is inactive in the most immature DN thymocytes, which probably use a distinct silencer mechanism to down-regulate CD4 gene expression. Unexpectedly, the CD4 silencer is also active in CD4+ CD8int/- cells of the thymus, implying that an anti-silencer may be required to resume CD4 expression in this cell population. Altogether, the CD4 gene is regulated by several positive and negative regulatory mechanisms which come into play in a developmentally coordinated manner.

expression

expression

expression

expression

double-negative

inhibits

expression

down-regulate

expression

resume

expression

regulated

double-positive

required

expression

required

resume

regulated

control

control

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Triggering of HLA-DR antigens differentially modulates tumor necrosis factor alpha release by B cells at distinct stage of maturation.
Triggering of HLA class II antigens by the anti-HLA-DR monoclonal antibody (mAb) L243 significantly (P < 0.05) and differentially enhanced the release of tumor necrosis factor alpha (TNF-alpha) by the non-Hodgkin's lymphoma cells Ri-I, Ci-I, and Sc-I, which are at a distinct stage of B-cell differentiation, and by the more mature Burkitt lymphoma cell Raji; in contrast, it did not induce TNF-alpha release by the pre-B leukemia cells Nalm-6 and BV173. TNF-alpha release peaked at 24 h and decreased thereafter, and it was dose dependent and preceded by an increase of TNF-alpha mRNA detectable after 3 h of stimulation with mAb L243. Secreted TNF-alpha mediated the enhancement of nuclear factor kappa B (NF-kappa B) and activator protein-1 (AP-1) binding activity; in fact, the triggering of HLA-DR antigens in the presence of antihuman TNF-alpha-neutralizing antibodies did not upregulate NF-kappa B and AP-1. In contrast, released TNF-alpha was not responsible for the homotypic aggregation of Ri-I, Ci-I, Sc-I, and Raji cells induced by mAb L243, and it did not affect the proliferation of B cells investigated. Altogether, our data demonstrate that: (a) the ability of B cells to release TNF-alpha after triggering of HLA-DR antigens depends on their stage of differentiation; (b) levels of released TNF-alpha seem to correlate with the stage of B-cell maturation but do not correlate with the amounts of cell surface HLA-DR antigens; (c) secreted TNF-alpha regulates the levels of expression of NF-kappa B and AP-1 by an autocrine loop; and (d) intracellular signals mediating TNF-alpha release by B cells are distinct from those regulating homotypic aggregation and proliferation.

tumor necrosis factor alpha

tumor necrosis factor alpha

TNF-alpha

TNF-alpha

TNF-alpha

TNF-alpha

TNF-alpha

TNF-alpha

TNF-alpha

TNF-alpha

TNF-alpha

TNF-alpha

TNF-alpha

release

tumor necrosis factor alpha

release

TNF-alpha

release

TNF-alpha

release

TNF-alpha

Secreted

TNF-alpha

released

TNF-alpha

release

TNF-alpha

levels of released

TNF-alpha

secreted

TNF-alpha

release

TNF-alpha

enhanced

release

induce

release

peaked

release

preceded

release

increase

increase

TNF-alpha

after

release

mediating

release

modulates

release

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Cytomegalovirus immediate early genes upregulate interleukin-6 gene expression.
BACKGROUND: The immediate early genes (IE) of human cytomegalovirus (CMV) can be expressed in monocytic cells and are known to regulate viral and cellular genes. Interleukin-6 (IL-6) plays a central role in numerous inflammatory and immune processes. Interleukin-6 levels are increased in lung transplant patients clinically diagnosed with CMV pneumonitis. The regulation of IL-6 is dependent on various stimuli that include lipopolysaccharide (LPS), viruses, and other cytokines. These studies examined the ability of CMV IE gene products to modulate IL-6 production. METHODS: THP-1 cells, a monocytic cell line, were transfected with the CMV IE genes. Interleukin-6 protein and IL-6 mRNA were measured in control and CMV immediate early transfected cells. Cotransfection of CMV IE genes and IL-6 chloramphenicol acetyl transferase (CAT) or IL-6 luciferase constructs were used to study IL-6 promoter activity. RESULTS: Interleukin-6 protein and mRNA production were significantly increased in cells transfected with the CMV IE genes and stimulated with LPS compared to LPS-stimulated control cells. Cytomegalovirus IE gene products significantly enhanced LPS stimulation of IL-6 promoter activity in both IL-6 CAT and IL-6 luciferase assays. A deletion construct that contains a NF-kappa B site but is missing the multiple response region demonstrated a continued increase in IL-6 luciferase activity in LPS-stimulated CMV transfected cells. CONCLUSION: Cytomegalovirus immediate early gene products significantly enhanced expression of IL-6 in LPS-stimulated cells. The increase in IL-6 luciferase activity occurs in the absence of the multiple response region, the area of the IL-6 promoter responsive to IL-1, TNF alpha, cyclic amp, and phorbol 12-myristate 13-acetate. The ability of CMV IE gene products to enhance IL-6 production may play an important role in immune inflammatory states associated with CMV infection.

promoter

promoter

chloramphenicol acetyl transferase

CAT

CAT

TNF alpha

expression

production

expression

production

upregulate

expression

increased

increased

production

enhanced

stimulation

stimulation

promoter

enhanced

expression

enhance

production

regulation

modulate

production

responsive

promoter

TNF alpha

responsive

promoter

production

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Homodimerization of the human interleukin 4 receptor alpha chain induces Cepsilon germline transcripts in B cells in the absence of the interleukin 2 receptor gamma chain.
The cytokines interleukin (IL)-4 and IL-13 play a critical role in inducing Cepsilon germline transcripts and IgE isotype switching in human B cells. The IL-4 receptor (IL-4R) in B cells is composed of two chains, the IL-4-binding IL-4Ralpha chain, which is shared with the IL-13R, and the IL-2Rgamma (gammac) chain, which is shared with IL-7R, IL-9R, and IL-15R. IL-4 induces Cepsilon germline transcripts and IgE isotype switching in B cells from patients with gammac chain deficiency. Induction of Cepsilon germline transcripts by IL-4 in B cells that lack the gammac chain may involve signaling via the IL-13R. Alternatively, the IL-4Ralpha chain may transduce intracellular signals that lead to Cepsilon gene transcription independently of its association with other chains. We show that ligand-induced homodimerization of chimeric surface receptors consisting of the extracellular and transmembrane domains of the erythropoietin receptor and of the intracellular domain of IL-4Ralpha induces Janus kinase 1 (Jak1) activation, STAT6 activation, and Cepsilon germline transcripts in human B cell line BJAB. Disruption of the Jak1-binding proline-rich Box1 region of IL-4Ralpha abolished signaling by this chimeric receptor. Furthermore, B cells transfected with a chimeric CD8alpha/IL-4Ralpha receptor, which is expressed on the cell surface as a homodimer, constitutively expressed Cepsilon germline transcripts. These results suggest that homodimerization of the IL-4Ralpha chain is sufficient to transduce Jak1-dependent intracellular signals that lead to IgE isotype switching.

interleukin 4 receptor alpha chain

interleukin 2 receptor gamma chain

interleukin (IL)-4

IL-4Ralpha chain

IL-2Rgamma (gammac) chain

gammac chain

gammac chain

IL-4Ralpha chain

erythropoietin

Janus kinase 1

chimeric CD8alpha/IL-4Ralpha receptor

IL-4Ralpha chain

Homodimerization

interleukin 4 receptor alpha chain

binding

IL-4Ralpha chain

as a homodimer

chimeric CD8alpha/IL-4Ralpha receptor

homodimerization

IL-4Ralpha chain

lack

gammac chain

transfected

chimeric CD8alpha/IL-4Ralpha receptor

expressed

chimeric CD8alpha/IL-4Ralpha receptor

deficiency

gammac chain

induces

activation

activation

transfected

transfected

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Characterization of peripheral blood T-lymphocytes transduced with HTLV-I Tax mutants with different trans-activating phenotypes.
Tax1, a transcriptional trans-activator of the Human T-cell leukemia virus type I (HTLV-I), induces the expression of many cellular genes through interaction with at least three distinct cellular transcription factors; CREB/ATF, NF-kappaB, and SRF. This Tax1-induced activation of cellular genes is considered to be a critical event in T-cell transformation by HTLV-I. To elucidate the role of each Tax1-inducible transcriptional pathway in T-cell transformation, we introduced Tax1 mutants with different trans-activating phenotypes into peripheral blood lymphocytes (PBL) by retroviral vectors. Analysis of these PBLs revealed that activation of the NF-kappaB pathway is sufficient to promote the growth response to IL-2. However, for the clonal expansion of CD4+ T-cells, which is a characteristic result of HTLV-I infection, activation of the CREB/ATF and SRF pathways is also required.

Tax

SRF

SRF

interaction

SRF

interaction

transduced

Tax

introduced

transduced

transduced

introduced

introduced

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Involvement of the N-terminal region of the human mineralocorticoid receptor hormone-binding domain in agonist and antagonist binding as revealed by a new monoclonal antibody.
To gain a better understanding of the mechanism of binding to the human mineralocorticoid receptor (hMR), we developed a new monoclonal antibody (mAb) raised against the hormone-binding domain (HBD). For this purpose, mice were immunized with a fusion protein including the sequence Thr729-Lys984 of hMR. After ELISA screening, mAb 18C7 was selected for its specificity towards the HBD. This antibody recognized both the denatured and native MR forms, as well as the hetero-oligomeric MR form and the transformed MR state. By using several HBD subfragments, the mAb 18C7 epitope was located in the N-terminal region of the HBD from Thr729 to Leu765. We then studied the effect of the antibody on aldosterone and progesterone binding to the hMR. When 18C7 was incubated with liganded MR, it was able to partly displace (20%) the hormone from its binding site. When 18C7 was incubated with MR before aldosterone or progesterone, the antibody inhibited 75-80% of the binding. The effect of 18C7 on the binding was similar with both hormones. A sucrose gradient analysis indicated the simultaneous presence of two kinds of receptor complexes: the steroid-MR complex and the antibody-MR complex. After its associated proteins, especially the heat-shock protein hsp90, had been cross-linked with the hMR by dimethylpimelimidate, 18C7 was still able to react with the receptor. Our results indicated that the epitope recognized by 18C7 was directly implicated in hormone binding. The lack of steroid binding of HBD mutants with the Thr729-Leu765 sequence deleted [Jalaguier, Mesnier, Leger and Auzou (1996) J.Steroid Biochem.Mol.Biol.57, 43-50] supports this hypothesis. Because of the similar behaviours of aldosterone and progesterone, we conclude that the N-terminal Thr729-Leu765 region of the HBD is similarly involved in the binding of both hormones.

mineralocorticoid receptor

mineralocorticoid receptor

MR

MR

MR

MR

MR

MR

MR

MR

MR

MR

hMR

binding

mineralocorticoid receptor

binding

MR

recognized

MR

recognized

MR

binding

MR

liganded

MR

binding

MR

binding

MR

complex

MR

complex

MR

cross-linked

hMR

binding

MR

binding

MR

inhibited

binding

still able to

cross-linked

react

effect

binding

effect

binding

react

hMR

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Abnormal T lymphocyte development induced by targeted overexpression of IkappaB alpha.
A role in thymic maturation for factors of the NF-kappaB family has long been suspected, but not yet proven. Transgenic mice with a lymphocyte-specific defect in NF-kappaB activation were produced by targeted expression of human IkappaB alpha. The thymic cellularity of these mice was significantly decreased. The proportion of mature, TCRhigh thymocytes of the alphabeta lineage was reduced, and the remaining TCRhigh population contained an unusually high proportion of double-positive cells. This defect in maturation resulted in a transgene dose-dependent reduction in peripheral T lymphocytes, with the CD8 lineage being more severely affected. These data provide direct evidence for the involvement of NF-kappaB/Rel family proteins in late stages of T lymphocyte development, coincident with positive and negative selection.

IkappaB alpha

IkappaB alpha

expression

IkappaB alpha

overexpression

IkappaB alpha

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Sequential development of structural and functional alterations in T cells from tumor-bearing mice.
The TCR alpha beta or -gamma delta chains bind the peptide ligand, whereas the associated CD3 deltaepsilongamma and TCR zeta subunits couple the TCR to intracellular signal transduction components. Recently, several groups have described marked alterations in signal transduction elements in T cells from cancer patients or in mice bearing tumor for a few weeks (>26 days). The sequence in which these alterations develop is unknown. The aim of this study was to explore the kinetics of the development of alterations in signal transduction molecules (TCR zeta chain, NF kappaB family proteins, and tyrosine kinase p56(lck)) in mice bearing MC38 colon adenocarcinoma. The results demonstrate that alterations in NF kappaB family proteins, specifically the failure of p65 translocation to the nucleus, occur earlier and more frequently than the decrease in zeta-chain. These defects are paralleled by an impaired ability to produce Th1 cytokines (IL-2 and IFN-gamma). These initial changes are followed by the eventual loss of TCR zeta chain and p56(lck) and a marked decrease in cytotoxic function. An increased rate of lysosomal degradation is one of the mechanisms responsible for the loss of zeta-chain.

nucleus

CD3 delta

epsilon

gamma

TCR zeta

TCR zeta chain

tyrosine kinase p56(lck)

IFN-gamma

TCR zeta chain

produce

produce

IFN-gamma

translocation

nucleus

failure

translocation

decrease

TCR zeta chain

impaired ability

produce

loss

TCR zeta chain

loss

occur

failure

paralleled

failure

impaired ability

followed

impaired ability

loss

followed

failure

loss

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
An isotype-specific activator of major histocompatibility complex (MHC) class II genes that is independent of class II transactivator.
Patients with one type of major histocompatibility complex class II combined immunodeficiency have mutations in a gene termed class II transactivator (CIITA), which coordinately controls the transcription of the three major human class II genes, HLA-DR, -DQ, and -DP. However, the experimentally derived B-lymphoblastoid cell line, clone 13, expresses high levels of HLADQ in the absence of HLA-DR and HLA-DP, despite its mapping by complementation analysis to this group. It was possible that one of the clone 13 CIITA alleles bore a mutation that allowed HLA-DQ, but not HLA-DR or -DP transcription. Alternatively, another factor, distinct from CIITA, might control HLA-DQ expression. We report here that ectopic expression of CIITA cDNAs derived by reverse transcriptase polymerase chain reaction from clone 13 do not restore expression of HLA-DQ in another CIITA-deficient cell line, RJ2.2.5. In addition, no CIITA protein is detectable in clone 13 nuclear extracts. In contrast, somatic cell fusion between clone 13 and RJ2.2.5 restored expression of the HLA-DQ haplotype encoded by the RJ2.2.5 DQB gene. Taken together, these data demonstrate the existence of an HLA-DQ isotype-specific trans-acting factor, which functions independently of CIITA.

class II transactivator

class II transactivator

CIITA

CIITA

CIITA

CIITA

CIITA

CIITA

CIITA

expression

CIITA

detectable

CIITA

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
Induction of cytokine expression in leukocytes by binding of thrombin-stimulated platelets.
BACKGROUND: Activated platelets tether and activate myeloid leukocytes. To investigate the potential relevance of this mechanism in acute myocardial infarction (AMI), we examined cytokine induction by leukocyte-platelet adhesion and the occurrence of leukocyte-platelet conjugates in patients with AMI. METHODS AND RESULTS: We obtained peripheral venous blood samples in 20 patients with AMI before and daily for 5 days after direct percutaneous transluminal coronary angioplasty (PTCA) and in 20 patients undergoing elective PTCA. Throughout the study period, CD41 immunofluorescence of leukocytes (flow cytometry) revealed increased leukocyte-platelet adhesion in patients with AMI compared with control patients (mean +/- SE of fluorescence [channels] before PTCA: 77 +/- 16 versus 35 +/- 9; P = .003). In vitro, thrombin-stimulated fixed platelets bound to neutrophils and monocytes. Within 2 hours, this resulted in increased mRNA for interleukin (IL),1 beta, IL-8, and monocyte chemoattractant protein (MCP)-1 in unfractionated leukocytes. After 4 hours, IL-1 beta and IL-8 concentration of the cell-free supernatant had increased by 268 +/- 36% and 210 +/- 7%, respectively, and cellular MCP-1 content had increased by 170 +/- 8%. Addition of activated platelets to adherent monocytes had a similar effect and was associated with nuclear factor-kappa B activation. Inhibition of binding by anti-P selectin antibodies reduced the effect of activated platelets on cytokine production. CONCLUSIONS: In patients with AMI, leukocyte-platelet adhesion is increased. Binding of activated platelets induces IL-1 beta, IL-8, and MCP-1 in leukocytes. Our findings suggest that leukocyte-platelet adhesion contributes to the regulation of inflammatory responses in AMI.

thrombin

interleukin (IL),1 beta

monocyte chemoattractant protein (MCP)-1

IL-1 beta

P selectin

IL-1 beta

resulted in increased

interleukin (IL),1 beta

resulted in increased

resulted in increased

monocyte chemoattractant protein (MCP)-1

increased

IL-1 beta

increased

increased

induces

IL-1 beta

induces

induces

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.


Input:
The class II trans-activator CIITA interacts with the TBP-associated factor TAFII32.
The class II trans- activator (CIITA) is the main transcriptional co-activator for the expression of MHC class II proteins. Its N-terminal 125 amino acids function as an independent transcriptional activation domain. Analyses of the primary amino acid sequence of the activation domain predict the presence of three alpha-helices, each with a high proportion of acidic residues. Using site-directed mutagenesis, we found that two of these predicted alpha-helices are required for full transcriptional activation by CIITA. Moreover, a CIITA protein in which both functional alpha-helices have been deleted displays a dominant negative phenotype. This activation domain of CIITA interacts with the 32 kDa subunit of the general transcription complex TFIID, TAFII32. Decreased transcriptional activation by N-terminal deletions of CIITA is correlated directly with their reduced binding to TAFII32. We conclude that interactions between TAFII32 and CIITA are responsible for activation of class II genes.

activation domain

class II trans-activator

CIITA

TBP

class II trans- activator

CIITA

CIITA

CIITA

CIITA

CIITA

CIITA

interacts

CIITA

interacts

activation domain

CIITA

binding

CIITA

interactions

CIITA

displays a dominant negative phenotype

CIITA

reduced

binding

A generic non-protein physical entity used as an event site or location argument.

A gene or gene-product mention, represented by the GENIA Protein label.

Association of two or more biological participants.

The site on the theme where the event occurs; Site2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme2 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme3 distinguishes an additional filler of the same role.

The primary participant or event affected by the event; Theme4 distinguishes an additional filler of the same role.

Expression or production of a gene product.

Presence or movement of a biological participant at or to a location.

The location at which the event or its theme is situated.

The destination location to which a participant moves.

Regulation that decreases, suppresses, or prevents its theme.

The site on the cause that participates in a regulatory event.

The participant or event responsible for causing or regulating the event.

The site on the theme where the event occurs.

The primary participant or event affected by the event.

Addition of a phosphate group to a biological molecule.

Regulation that increases, promotes, or enables its theme.

Degradation or catabolic processing of a protein.

Regulation whose positive or negative direction is not specified.

Transcription of a gene or DNA template into RNA.