Input:
v-erbA overexpression is required to extinguish c-erbA function in erythroid cell differentiation and regulation of the erbA target gene CAII.
The v-erbA oncoprotein represents a retrovirus-transduced oncogenic version of the thyroid hormone (T3/T4) receptor c-erbA (type alpha). It contributes to virus-induced erythroleukemia by efficiently arresting differentiation of red cell progenitors and by suppressing transcription of erythrocyte-specific genes. Here, we show that v-erbA and c-erbA bind directly to sequences within the promoter of the erythrocyte-specific carbonic anhydrase II (CAII), a gene whose transcription is efficiently suppressed by v-erbA. This erbA-binding site confers thyroid hormone responsiveness to a heterologous promoter in transient expression experiments and is a target for efficient down-regulation of CAII transcription by the v-erbA oncoprotein. In stably transformed erythroblasts coexpressing the v-erbA oncoprotein and the c-erbA/T3 receptor at an approximately equimolar ratio, c-erbA activity is dominant over v-erbA. T3 efficiently induced erythroid differentiation in these cells, thus overcoming the v-erbA-mediated differentiation arrest. Likewise, T3 activated CAII transcription as well as transient expression of a T3-responsive reporter gene containing the CAII-specific erbA-binding site. The c-erbA-dependent activation of this CAII reporter construct could only be suppressed by very high amounts of v-erbA. Our results suggest that overexpression of v-erbA is required for its function as an oncoprotein.

v-erbA

c-erbA

CAII

v-erbA

c-erbA

v-erbA

c-erbA

carbonic anhydrase II

CAII

v-erbA

CAII

v-erbA

v-erbA

c-erbA

c-erbA

v-erbA

v-erbA

CAII

CAII

c-erbA

CAII

v-erbA

v-erbA

bind

v-erbA

CAII

bind

c-erbA

CAII

overexpression

v-erbA

coexpressing

v-erbA

coexpressing

c-erbA

overexpression

v-erbA

extinguish

overexpression

regulation

suppressed

transcription

v-erbA

down-regulation

transcription

activated

transcription

overexpression

overexpression

required

overexpression

v-erbA

regulation

c-erbA

CAII

target

down-regulation

v-erbA

transcription

CAII

transcription

CAII

transcription

CAII

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:
NF-X2 that binds to the DRA X2-box is activator protein 1. Expression cloning of c-Jun.
Human class II MHC Ag are a family of cell surface glycoproteins. Their constitutive expression is limited to B lymphocytes and thymic epithelial cells. In many other cells their expression can be induced by IFN-gamma. Conserved upstream promoter sequences regulate this tissue-specific expression of class II genes. In the DRA promoter, one of these cis-acting regulatory motifs is the X2-box to which nuclear factor X2 (NF-X2) binds. Here, we present the isolation and characterization of the full-length cDNA clone encoding NF-X2. This cDNA clone was isolated by expression cDNA cloning, and encodes the human c-Jun protein, which together with c-Fos forms the heterodimeric activator protein-1 transcription complex. Whereas c-Fos/c-Jun heterodimers do not exist in B cells, they form and bind to the X2-box in class II nonexpressing cells. Thus, c-Fos/c-Jun heterodimers might contribute to the repression of DRA gene expression.

c-Jun

IFN-gamma

c-Jun

c-Fos

c-Fos

c-Jun

c-Fos

c-Jun

DRA

complex

c-Jun

c-Fos

form

c-Fos

c-Jun

bind

c-Fos

bind

c-Jun

exist

c-Fos

exist

c-Jun

expression

DRA

repression

c-Fos

expression

repression

c-Jun

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 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:
Regulation of jun and fos gene expression in human monocytes by the macrophage colony-stimulating factor.
The macrophage colony-stimulating factor (M-CSF) is required for the growth and differentiation of mononuclear phagocytes. However, the signaling events responsible for these effects remain unclear. The present studies have examined the effects of M-CSF on potential signaling pathways involving expression of the jun and fos early response genes. Low levels of c-jun transcripts were detectable in resting human peripheral blood monocytes. Treatment of these cells with 10(3) units/ml human recombinant M-CSF was associated with rapid and transient increases in c-jun mRNA levels. Nuclear run-on assays and mRNA stability studies demonstrated that M-CSF regulates c-jun expression by both an increase in transcription rate and a prolongation in the half-life of c-jun transcripts. M-CSF treatment was also associated with a rapid induction of the jun-B gene, although expression of this gene was prolonged compared to that of c-jun. We further demonstrate that M-CSF increases c-fos mRNA levels in human monocytes through control at both the transcriptional and posttranscriptional levels. Maximal induction of the c-fos gene was followed by that for the fos-B gene. Moreover, M-CSF-induced expression of the fos-related gene, fra-1, was delayed compared to that for both c-fos and fos-B. Taken together, the results indicate that M-CSF treatment is associated with differential activation of multiple members of the jun/fos family and that expression of these genes could contribute to nuclear signaling mechanisms that regulate a specific program of monocyte differentiation.

jun

fos

jun

fos

c-jun

c-jun

c-jun

c-jun

jun-B

c-jun

c-fos

c-fos

fos-B

c-fos

fos-B

gene expression

jun

gene expression

fos

expression

jun

expression

fos

expression

c-jun

expression

c-jun

expression

jun-B

expression

expression

c-fos

expression

fos-B

detectable

transcripts

increases

levels

increase

transcription

prolongation in the half-life

c-jun

induction

jun-B

prolonged

expression

increases

c-fos

induction

c-fos

induction

fos-B

induced

expression

Regulation

gene expression

effects

involving

involving

expression

regulates

expression

transcripts

c-jun

levels

c-jun

transcription

c-jun

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:
cAMP-dependent regulation of proenkephalin by JunD and JunB: positive and negative effects of AP-1 proteins.
We demonstrate that JunD, a component of the AP-1 transcription factor complex, activates transcription of the human proenkephalin gene in a fashion that is completely dependent upon the cAMP-dependent protein kinase, protein kinase A. Activation of proenkephalin transcription by JunD is dependent upon a previously characterized cAMP-, phorbol ester-, and Ca(2+)-inducible enhancer, and JunD is shown to bind the enhancer as a homodimer. Another component of the AP-1 transcription complex, JunB, is shown to inhibit activation mediated by JunD. As a homodimer JunB is unable to bind the enhancer; however in the presence of c-Fos, high-affinity binding is observed. Furthermore, JunD is shown to activate transcription of genes linked to both cAMP and phorbol ester response elements in a protein kinase A-dependent fashion, further blurring the distinction between these response elements. These results demonstrate that the transcriptional activity of an AP-1-related protein is regulated by the cAMP-dependent second-messenger pathway and suggest that JunD and other AP-1-related proteins may play an important role in the regulation of gene expression by cAMP-dependent intracellular signaling pathways.

JunD

JunB

JunD

JunD

JunD

JunB

JunD

JunB

c-Fos

JunD

JunD

bind

JunD

bind

JunB

binding

JunB

in the presence of

c-Fos

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.


Input:
Induction of monocytic differentiation and NF-kappa B-like activities by human immunodeficiency virus 1 infection of myelomonoblastic cells.
The effects of human immunodeficiency virus 1 (HIV-1) infection on cellular differentiation and NF-kappa B DNA binding activity have been investigated in a new model of myeloid differentiation. PLB-985 cells represent a bipotential myelomonoblastic cell population capable of either granulocytic or monocytic differentiation after induction with appropriate inducers. By virtue of the presence of CD4 on the cell surface, PLB-985 cells were chronically infected with HIV-1 strain IIIB. PLB-IIIB cells clearly possessed a more monocytic phenotype than the parental myeloblasts, as determined by differential staining, increased expression of the myeloid-specific surface markers, and transcription of the c-fms proto-oncogene. NF-kappa B binding activity was inducible by tumor necrosis factor and phorbol myristate acetate in PLB-985. However, in PLB-IIIB cells, constitutive expression of a novel NF-kappa B complex was detected, composed of proteins ranging between 70 and 110 kD. These proteins interacted specifically with the symmetric NF-kappa B site from the interferon beta (IFN-beta) promoter. Mutations affecting the 5' guanine residues of the kappa B site were unable to compete for these NF-kappa B-related proteins. Inducibility of endogenous IFN-beta and IFN-alpha RNA was also increased in PLB-IIIB cells. These studies indicate that HIV-1 infection of myelomonoblastic cells may select for a more mature monocytic phenotype and that unique subunit associations of NF-kappa B DNA binding proteins may contribute to differential NF-kappa B-mediated gene expression.

symmetric NF-kappa B site

c-fms

interferon beta

IFN-beta

IFN-beta

IFN-alpha

interacted

symmetric NF-kappa B site

interferon beta

increased

transcription

increased

Inducibility

transcription

c-fms

Inducibility

IFN-beta

Inducibility

IFN-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:
The AP-1 site at -150 bp, but not the NF-kappa B site, is likely to represent the major target of protein kinase C in the interleukin 2 promoter.
Stimulation of T cells with antigen results in activation of several kinases, including protein kinase C (PKC), that may mediate the later induction of activation-related genes. We have examined the potential role of PKC in induction of the interleukin 2 (IL-2) gene in T cells stimulated through the T cell receptor/CD3 complex. We have previously shown that prolonged treatment of the untransformed T cell clone Ar-5 with phorbol esters results in downmodulation of the alpha and beta isozymes of PKC, and abrogates induction of IL-2 mRNA and protein. Here we show that phorbol ester treatment also abolishes induction of chloramphenicol acetyltransferase activity in Ar-5 cells transfected with a plasmid containing the IL-2 promoter linked to this reporter gene. The IL-2 promoter contains binding sites for nuclear factors including NFAT-1, Oct, NF-kappa B, and AP-1, which are all potentially sensitive to activation of PKC. We show that induction of a trimer of the NFAT and Oct sites is not sensitive to phorbol ester treatment, and that mutations in the NF-kappa B site have no effect on inducibility of the IL-2 promoter. In contrast, mutations in the AP-1 site located at -150 bp almost completely abrogate induction of the IL-2 promoter, and appearance of an inducible nuclear factor binding to this site is sensitive to PKC depletion. Moreover, cotransfections with c-fos and c-jun expression plasmids markedly enhance induction of the IL-2 promoter in minimally stimulated T cells. Our results indicate that the AP-1 site at -150 bp represents a major, if not the only, site of PKC responsiveness in the IL-2 promoter.

promoter

promoter

promoter

interleukin 2

interleukin 2

chloramphenicol acetyltransferase

c-fos

c-jun

induction

expression

c-fos

expression

c-jun

abrogates

induction

abolishes

induction

abrogate

induction

induction

chloramphenicol acetyltransferase

inducibility

promoter

induction

promoter

enhance

expression

induction

induction

promoter

role

induction

effect

inducibility

induction

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 role of jun and fos gene family members in 12-O-tetradecanoylphorbol-13-acetate induced hemopoietic differentiation.
Terminal differentiation of the leukemic cell lines U-937 and HL-60 by 12-O-tetradecanoylphorbol-13-acetate is accompanied by marked changes in gene expression. In this study, we demonstrate that the expression of jun and fos gene family members is induced with variable kinetics during 12-O-tetradecanoylphorbol-13-acetate induced differentiation, with c-jun expression best paralleling differentiation. The generation of AP-1 complexes, as measured by DNA binding activity, closely parallels morphological differentiation. Furthermore, the ability of these complexes to regulate gene expression is demonstrated by increased transcription from an AP-1 driven reporter construct and marked increases in the expression of endogenous AP-1 regulated genes. Differentiation assays using water soluble phorbol esters reveal that differentiation becomes irreversible soon after AP-1 appears. This tight correlation between c-jun expression, the generation of AP-1 activity, and differentiation suggests a critical role for this gene and transcriptional complex during this process.

c-jun

c-jun

expression

c-jun

expression

c-jun

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 a cofactor that regulates dimerization of a mammalian homeodomain protein.
Dimerization among transcription factors has become a recurrent theme in the regulation of eukaryotic gene expression. Hepatocyte nuclear factor-1 alpha (HNF-1 alpha) is a homeodomain-containing protein that functions as a dimer. A dimerization cofactor of HNF-1 alpha (DCoH) was identified that displayed a restricted tissue distribution and did not bind to DNA, but, rather, selectively stabilized HNF-1 alpha dimers. The formation of a stable tetrameric DCoH-HNF-1 alpha complex, which required the dimerization domain of HNF-1 alpha, did not change the DNA binding characteristics of HNF-1 alpha, but enhanced its transcriptional activity. However, DCoH did not confer transcriptional activation to the GAL4 DNA binding domain. These results indicate that DCoH regulates formation of transcriptionally active tetrameric complexes and may contribute to the developmental specificity of the complex.

Hepatocyte nuclear factor-1 alpha

HNF-1 alpha

dimerization cofactor of HNF-1 alpha

DCoH

HNF-1 alpha

DCoH

HNF-1 alpha

HNF-1 alpha

HNF-1 alpha

DCoH

DCoH

bind

DCoH

complex

DCoH

HNF-1 alpha

binding

HNF-1 alpha

distribution

DCoH

stabilized

DCoH

HNF-1 alpha

required

complex

change

complex

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.


Input:
Nuclear factor kappa B activates proenkephalin transcription in T lymphocytes.
Upon activation, T lymphocytes accumulate high levels of the neuropeptide enkephalin which correlate with high levels of proenkephalin mRNA in the cells. Here we investigated the transcriptional basis for these changes. The proenkephalin promoter contains a sequence GGGGACGTCCCC, named B2, which is similar to the kappa B sequence GGGGACTTTCC, the binding site of the transcription factor nuclear factor (NF)-kappa B. Activation of T lymphocytes induces an NF-kappa B-like binding activity to the B2 site, concomitant with activation of the proenkephalin promoter. Mutations at the B2 site abolish this transcriptional activation. The purified homodimer (two p50s) of the DNA-binding subunit of NF-kappa B binds the B2 site of proenkephalin relatively better than does the heterotetramer (two p65s plus two p50s) form of the factor. Thus, it appears that the T-cell-specific activation of the proenkephalin promoter is mediated by NF-kappa B. However, as NF-kappa B is ubiquitous and the transcriptional activation through the B2 site is T cell specific, yet another T-cell-specific factor which synergizes with NF-kappa B should be considered.

promoter

B2 site

promoter

proenkephalin

proenkephalin

proenkephalin

proenkephalin

proenkephalin

proenkephalin

homodimer

binds

B2 site

proenkephalin

heterotetramer

abolish

activation

activates

transcription

activation

proenkephalin

promoter

activation

proenkephalin

promoter

mediated

activation

transcription

proenkephalin

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:
ETS1 transactivates the human GM-CSF promoter in Jurkat T cells stimulated with PMA and ionomycin.
Activation of T helper cells results in coordinate expression of a number of cytokines involved in differentiation, proliferation and activation of the haematopoietic system. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is one such cytokine whose increased expression results partly from increases in transcription. Cis-acting elements with NF kappa B, AP-1 and ETS-like motifs have been identified in the promoter region of the GM-CSF gene, which are important for transcriptional activity following PMA and ionomycin stimulation. A number of the ETS family of transcription factors are expressed in T cells, including ETS1 and ELF1. Here we describe the ability of these factors to interact with a site (GM5), located within the CLE0 element, -47 to -40 upstream of the GM-CSF transcription initiation site. Exogenous ETS1, but not ELF1, can transactivate GM-CSF, through the GM5 site, in a PMA/ionomycin dependent manner. Other unidentified ETS-like factors present in Jurkat cells are also capable of binding GM5. Mutation of the core ETS binding site from -GGAA- to -GGAT- prevents the binding of ETS-like factors with the exception of ETS1. The GM-CSF promoter, modified in this way to be ETS1 specific, is fully responsive to PMA/ionomycin induction, in addition to ETS1 transactivation in the presence of PMA and ionomycin. Together these data suggest that ETS1 may be involved in mediating the increased GM-CSF production associated with T cell activation.

promoter

promoter

GM-CSF

Granulocyte-macrophage colony-stimulating factor

GM-CSF

GM-CSF

GM-CSF

GM-CSF

GM-CSF

GM-CSF

interact

interact

binding

specific

GM-CSF

promoter

expression

GM-CSF

expressed

expressed

production

GM-CSF

exception

binding

transactivates

GM-CSF

promoter

increased

expression

increases

increases

transcription

transactivate

GM-CSF

transactivate

GM-CSF

induction

GM-CSF

promoter

transactivation

mediating

increased

increased

production

involved

mediating

transcription

GM-CSF

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:
Tissue-specific regulation of the rabbit 15-lipoxygenase gene in erythroid cells by a transcriptional silencer.
The 15-lipoxygenase (lox) gene is expressed in a tissue-specific manner, predominantly in erythroid cells but also in airway epithelial cells and eosinophils. We demonstrate in this report that the 5' flanking DNA of the 15-lox gene contains sequences which down-regulate its activity in a variety of non-erythroid cell lines but not in two erythroid cell lines. The element has characteristics of a transcriptional 'silencer' since it functions in both orientations. The main activity of the silencer has been mapped to the first 900 bp of 5' flanking DNA, which contains nine binding sites for a nuclear factor present in non-erythroid cells but not in erythroid cells. These binding sites have similar sequences and multiple copies of the binding sites confer tissue-specific down-regulation when attached to a minimal lox promoter fragment. The 5' flanking DNA also contains a cluster of three binding sites for the GATA family of transcription factors.

lox

lox

expressed

lox

down-regulate

expressed

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:
Coexpression of NF-kappa B/Rel and Sp1 transcription factors in human immunodeficiency virus 1-induced, dendritic cell-T-cell syncytia.
Productive infection of T cells with human immunodeficiency virus 1 (HIV-1) typically requires that the T cells be stimulated with antigens or mitogens. This requirement has been attributed to the activation of the transcription factor NF-kappa B, which synergizes with the constitutive transcription factor Sp1 to drive the HIV-1 promoter. Recently, we have found that vigorous replication of HIV-1 takes place in nonactivated memory T cells after syncytium formation with dendritic cells (DCs). These syncytia lack activated cells as determined by an absence of staining for Ki-67 cell cycle antigen. The expression and activity of NF-kappa B and Sp1 were, therefore, analyzed in isolated T cells and DCs from humans and mice. We have used immunolabeling, Western blot analysis, and electrophoretic mobility shift and supershift assays. T cells lack active NF-kappa B but express Sp1 as expected. DCs express high levels of all known NF-kappa B and Rel proteins, with activity residing primarily within RelB, p50, and p65. However, DCs lack Sp1, which may explain the failure of HIV-1 to replicate in purified DCs. Coexpression of NF-kappa B and Sp1 occurs in the heterologous DC-T-cell syncytia that are induced by HIV-1. Therefore, HIV-1-induced cell fusion brings together factors that upregulate virus transcription. Since DCs and memory T cells frequently traffic together in situ, these unusual heterologous syncytia could develop in infected individuals and lead to chronic HIV-1 replication without ostensible immune stimulation.

RelB

Coexpression

expression

express

lack

Coexpression

activity

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:
Costimulation requirement for AP-1 and NF-kappa B transcription factor activation in T cells.
The transcriptional activity of the IL-2 promoter requires T-cell costimulation delivered by the TCR and the auxiliary receptor CD28. Several transcription factors participate in IL-2 promoter activation, among which are AP-1-like factors and NF-kappa B. Protein phosphorylation has an important role in the regulation of these two factors: (1) it induces the transactivating capacity of the AP-1 protein c-Jun; and (2) it is involved in the release of the cytoplasmic inhibitor, I kappa B, from NF-kappa B, allowing translocation of the latter into the nucleus. We have recently shown that both phosphorylation processes require T-cell costimulation. Furthermore, in activated T cells, the kinetics of the two phosphorylation events are essentially similar. According to our results, however, the kinases responsible for the two processes are distinct entities. Whereas TPCK inhibits phosphorylation of I kappa B and, consequently, activation of NF-kappa B, it markedly enhances the activity of JNK, the MAP kinase-related kinase that phosphorylates the transactivation domain of c-Jun. We, therefore, propose the activation scheme presented in FIGURE 3 for T-cell costimulation. Costimulation results in the activation of a signaling pathway that leads to the simultaneous induction of the two transcription factors, AP-1 and NF-kappa B. Integration of the signals generated by TCR and CD28 engagement occurs along this pathway, which then bifurcates to induce I kappa B phosphorylation and NF-kappa B activation on the one hand, and JNK activation and c-Jun phosphorylation on the other. We are currently engaged in defining where the two signals integrate along the AP-1/NF-kappa B pathway.

promoter

c-Jun

c-Jun

c-Jun

phosphorylates

c-Jun

phosphorylation

c-Jun

requires

transcriptional activity

activation

promoter

induce

phosphorylation

participate

activation

transcriptional activity

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:
Cupric ion blocks NF kappa B activation through inhibiting the signal-induced phosphorylation of I kappa B alpha.
A transcription factor NF kappa B, which regulates expression of various cellular genes involved in immune responses and viral genes including HIV, is sequestered in the cytoplasm as a complex with an inhibitory protein I kappa B. Various extracellular signals induce phosphorylation and rapid degradation of I kappa B alpha to release NF kappa B. Cu2+ was found to inhibit the activation of NF kappa B induced by TNF-alpha, TPA, or H2O2. Deoxycholate treatment of the cytoplasmic extract prepared from cells stimulated by TNF-alpha in the presence of Cu2+ resulted in the release of NF kappa B from I kappa B alpha, indicating that Cu2+ interferes with the dissociation of the NF kappa B-I kappa B complex. Neither phosphorylation nor degradation of I kappa B alpha was observed upon TNF-alpha stimulation in the presence of Cu2+. These results indicate that Cu2+ inhibits the release of NF kappa B by blockade of a signal leading to the phosphorylation of I kappa B alpha.

I kappa B alpha

inhibitory protein I kappa B

I kappa B alpha

TNF-alpha

TNF-alpha

I kappa B alpha

I kappa B

I kappa B alpha

TNF-alpha

I kappa B alpha

complex

inhibitory protein I kappa B

inhibiting

phosphorylation

blockade

leading

phosphorylation

I kappa B alpha

phosphorylation

I kappa B alpha

phosphorylation

I kappa B alpha

phosphorylation

I kappa B alpha

induce

induce

degradation

induce

phosphorylation

in the presence of

phosphorylation

in the presence of

degradation

leading

phosphorylation

degradation

I kappa B alpha

degradation

I kappa B 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:
Salicylates inhibit lipopolysaccharide-induced transcriptional activation of the tissue factor gene in human monocytic cells.
Binding of plasma Factor VII/VIIa to the tissue factor (TF) receptor initiates the coagulation protease cascades. TF expression by circulating monocytes is associated with thrombotic and inflammatory complications in a variety of diseases. Transcriptional activation of the human TF gene in monocytic cells exposed to bacterial lipopolysaccharide (LPS) is mediated by binding of c-Rel/p65 heterodimers to a kappa B site in the TF promoter. Here, we report that a family of anti-inflammatory agents, known as the salicylates, inhibited LPS induction of TF activity and TF gene transcription in human monocytes and monocytic THP-1 cells at clinically relevant doses. Furthermore, sodium salicylate blocked the LPS-induced proteolytic degradation of I kappa B alpha, which prevented the nuclear translocation of c-Rel/p65 heterodimers. In contrast, two other nonsteroidal anti-inflammatory drugs, ibuprofen and indomethacin, did not inhibit LPS induction of the TF gene. These results indicated that salicylates inhibited LPS induction of TF gene transcription in monocytic cells by preventing nuclear translocation of c-Rel/p65 heterodimers. The clinical benefits of salicylates in the treatment of several diseases, including atherosclerosis and rheumatoid arthritis, may be related to their ability to reduce monocyte gene expression.

promoter

nuclear

nuclear

Factor VII/VIIa

tissue factor (TF) receptor

TF

TF

c-Rel

TF

TF

TF

I kappa B alpha

c-Rel

TF

TF

c-Rel

Binding

Factor VII/VIIa

tissue factor (TF) receptor

binding

c-Rel

TF

promoter

binding

TF

promoter

expression

TF

translocation

nuclear

c-Rel

translocation

nuclear

translocation

nuclear

c-Rel

translocation

nuclear

inhibited

induction

blocked

induced

prevented

blocked

translocation

inhibit

induction

inhibited

induction

preventing

preventing

translocation

Transcriptional activation

TF

mediated

Transcriptional activation

binding

induction

transcription

induced

proteolytic degradation

induction

TF

induction

transcription

proteolytic degradation

I kappa B alpha

transcription

TF

transcription

TF

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:
CIITA activates the expression of MHC class II genes in mouse T cells.
It has long been a puzzle that MHC class II molecules are expressed in human T cells after activation but not in mouse T cells; this expression is believed to play a role in the cell mediated immune response. Recently the MHC class II transactivator (CIITA) has been reported to be a major regulatory factor for both the constitutive and IFN inducible expression of MHC class II genes. Here we show that human T cells expressing MHC class II have CIITA transcripts while MHC class II-negative human T cells and mouse T cells do not. The expression of MHC class II genes in mouse T cells can be reconstituted upon transfection with the human CIITA cDNA. These data indicate that the expression of CIITA explains the expression or lack of expression of MHC class II in human and mouse T cells respectively.

CIITA

MHC class II transactivator

CIITA

CIITA

CIITA

CIITA

transfection

CIITA

expression

CIITA

transfection

transfection

have

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:
Identification of an I kappa B alpha-associated protein kinase in a human monocytic cell line and determination of its phosphorylation sites on I kappa B alpha.
Nuclear factor kappa B (NF-kappa B) is stored in the cytoplasm as an inactive form through interaction with I kappa B. Stimulation of cells leads to a rapid phosphorylation of I kappa B alpha, which is presumed to be important for the subsequent degradation. We have recently reported the establishment of a lipopolysaccharide (LPS)-dependent cell-free activation system of NF-kappa B in association with the induction of I kappa B alpha phosphorylation. In this study, we have identified a kinase in cell extracts from the LPS-stimulated human monocytic cell line, THP-1, that specifically binds and phosphorylates I kappa B alpha. LPS stimulation transiently enhanced the I kappa B alpha-bound kinase activity in THP-1 cells. Mutational analyses of I kappa B alpha and competition experiments with the synthetic peptides identified major phosphorylation sites by the bound kinase as Ser and Thr residues in the C-terminal acidic domain of I kappa B alpha. Moreover, we show that the peptide, corresponding to the C-terminal acidic domain of I kappa B alpha, blocked the LPS-induced NF-kappa B activation as well as inducible phosphorylation of endogenous I kappa B alpha in a cell-free system using THP-1 cells. These results suggested that the bound kinase is involved in the signaling pathway of LPS by inducing the phosphorylation of the C-terminal region of I kappa B alpha and subsequent dissociation of the NF-kappa B.I kappa B alpha complex.

C-terminal region

I kappa B alpha

I kappa B alpha

I kappa B alpha

I kappa B alpha

I kappa B alpha

I kappa B alpha

I kappa B alpha

I kappa B alpha

I kappa B alpha

I kappa B alpha

I kappa B alpha

I kappa B alpha

binds

I kappa B alpha

bound

I kappa B alpha

complex

I kappa B alpha

blocked

phosphorylation

phosphorylation

I kappa B alpha

phosphorylation

I kappa B alpha

phosphorylates

I kappa B alpha

phosphorylation sites

I kappa B alpha

phosphorylation

I kappa B alpha

phosphorylation

C-terminal region

I kappa B alpha

leads

phosphorylation

be important

phosphorylation

degradation

induction

phosphorylation

enhanced

bound

by

phosphorylation sites

inducing

phosphorylation

degradation

I kappa B 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:
Triggering of the human interleukin-6 gene by interferon-gamma and tumor necrosis factor-alpha in monocytic cells involves cooperation between interferon regulatory factor-1, NF kappa B, and Sp1 transcription factors.
We investigated the molecular basis of the synergistic induction by interferon-gamma (IFN-gamma)/tumor necrosis factor-alpha (TNF-alpha) of human interleukin-6 (IL-6) gene in THP-1 monocytic cells, and compared it with the basis of this induction by lipopolysaccharide (LPS). Functional studies with IL-6 promoter demonstrated that three regions are the targets of the IFN-gamma and/or TNF-alpha action, whereas only one of these regions seemed to be implicated in LPS activation. The three regions concerned are: 1) a region between -73 and -36, which is the minimal element inducible by LPS or TNF-alpha; 2) an element located between -181 and -73, which appeared to regulate the response to IFN-gamma and TNF-alpha negatively; and 3) a distal element upstream of -224, which was inducible by IFN-gamma alone. LPS signaling was found to involve NF kappa B activation by the p50/p65 heterodimers. Synergistic induction of the IL-6 gene by IFN-gamma and TNF-alpha, in monocytic cells, involved cooperation between the IRF-1 and NF kappa B p65 homodimers with concomitant removal of the negative effect of the retinoblastoma control element present in the IL-6 promoter. This removal occurred by activation of the constitutive Sp1 factor, whose increased binding activity and phosphorylation were mediated by IFN-gamma.

promoter

interferon-gamma

tumor necrosis factor-alpha

interferon regulatory factor-1

interferon-gamma

IFN-gamma

tumor necrosis factor-alpha

TNF-alpha

IFN-gamma

TNF-alpha

TNF-alpha

IFN-gamma

TNF-alpha

IFN-gamma

IFN-gamma

TNF-alpha

IFN-gamma

binding activity

phosphorylation

Triggering

interferon-gamma

Triggering

tumor necrosis factor-alpha

induction

IFN-gamma

induction

TNF-alpha

induction

activation

activation

induction

IFN-gamma

induction

TNF-alpha

involved

induction

involved

induction

activation

increased

binding activity

mediated

increased

IFN-gamma

mediated

phosphorylation

IFN-gamma

involves cooperation

Triggering

interferon regulatory factor-1

involves cooperation

Triggering

action

promoter

IFN-gamma

action

promoter

TNF-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:
The lymphotoxin promoter is stimulated by HTLV-I tax activation of NF-kappa B in human T-cell lines.
The HTLV-I transcriptional activator tax was used to gain insight into the mechanism of lymphotoxin (LT; TNF-beta) gene induction. Tax-expressing cell lines produce LT biologic activity. An LT promoter (LT-293) CAT construct that contained an NF-kappa B site was active in the LT-producing C81-66-45 cell line, which contains defective HTLV-I but expresses tax. The observation that a mutated LT-kappa B construct (M1-CAT) was inactive in C81-66-45, confirmed the importance of NF-kappa B in LT gene expression. Tax was transfected into HTLV-I-negative human T-cell lines. Jurkat T cells stably expressing tax contained elevated levels of NF-kappa B that directly bound to the LT-kappa B site. Tax co-transfected with reporter constructs into Jurkat cells maximally activated HTLV-I-LTR-CAT and kappa B-fos-CAT and also activated LT-293 to a lesser extent. In JM T cells, tax induced LT-293 activity by two- to four-fold, though there was no induction of M1-CAT. The increase in LT-293 CAT activity mirrored the increase in LT biologic activity seen under these conditions. These studies, the first to demonstrate induction of LT promoter activity over basal levels, indicate that HTLV-I tax causes low-level activation of both endogenous LT and the LT promoter, at least in part through activation of NF-kappa B.

tax

tax

TNF-beta

CAT

tax

CAT

Tax

tax

Tax

CAT

fos

CAT

tax

CAT

CAT

tax

induction

TNF-beta

expresses

tax

expression

TNF-beta

expressing

tax

transfected

Tax

inactive

CAT

importance

expression

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:
Induction of tyrosine phosphorylation and T-cell activation by vanadate peroxide, an inhibitor of protein tyrosine phosphatases.
Rapid tyrosine phosphorylation of key cellular proteins is a crucial event in the transduction of activation signals to T-lymphocytes. The regulatory role of protein tyrosine phosphatases (PTPases) in this process was explored by studying the effects of a powerful PTPase inhibitor, vanadate peroxide (pervanadate), on the activation cascade of Jurkat human leukaemic T-cells. Pervanadate induced activation of the tyrosine kinases lck and fyn (4- and 3-fold respectively) and a dramatic increase in tyrosine phosphorylation of cellular proteins, notably phospholipase C gamma 1. After this event, we observed a rise in intracellular Ca2+ concentration, corresponding to an influx. This effect required surface expression of the CD45 PTPase and was not observed in CD45-deficient variants of Jurkat cells. In the CD45-negative variant, the effect of pervanadate on tyrosine phosphorylation was globally decreased and some phosphorylated substrates were specifically missing. Pervanadate also stimulated transcription of the c-fos gene and accumulation of its mRNA as well as several other hallmarks of T-lymphocyte activation such as surface expression of the CD69 antigen and the interleukin 2 receptor alpha-chain (CD25). Pervanadate synergized with signals delivered by T-cell antigen receptor engagement or by a phorbol ester to induce interleukin 2 production. Pervanadate activated NF-kappa B, as shown by an increase in DNA-binding activity of this transcription factor. We thus conclude that PTPases play a crucial role in the negative regulation of signal transduction culminating in T-lymphocyte activation. Moreover, induction of tyrosine phosphorylation appears sufficient per se to initiate a complete activation programme.

tyrosine

lck

fyn

phospholipase C gamma 1

c-fos

interleukin 2 receptor alpha-chain

interleukin 2

expression

expression

expression

phosphorylation

tyrosine

phospholipase C gamma 1

activation

lck

activation

fyn

increase

phosphorylation

stimulated

transcription

stimulated

accumulation

stimulated

expression

accumulation

c-fos

transcription

c-fos

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 interleukin-8 AP-1 and kappa B-like sites are genetic end targets of FK506-sensitive pathway accompanied by calcium mobilization.
FK506, an immunosuppressant, inhibits the production of several cytokines in T lymphocytes. We observed that FK506 suppressed the transcription of a chemotactic cytokine, interleukin-8 (IL-8) in a human T cell line, Jurkat cells, activated by phorbol 12-myristate 13-acetate (PMA) and calcium (Ca2+) ionophore (ionomycin). By deleted and mutated analysis of the IL-8 promoters, the AP-1 and kappa B-like sites were identified as the responsive elements for PMA and ionomycin. FK506 suppressed the transcriptions through the AP-1 or kappa B-like sites induced by PMA plus Ca(2+)-mobilizing agents, but not those induced by Ca(2+)-independent stimuli. In gel retardation analysis, FK506 had little effect on the binding to the AP-1 site of PMA/ionomycin-induced nuclear factors, which were recognized with anti-JunD or c-Fos antibody. In contrast, FK506 or EGTA (Ca2+ chelator) similarly affected the formation of kappa B-like site binding complexes, which were not recognized by any antibodies against the human Rel family proteins (c-Rel, p65, p50, and p49). Furthermore, we confirmed the previous report that FK506 suppressed the PMA/ionomycin-induced activation through authentic kappa B site of immunoglobulin (Ig) gene, to which NF-kappa B binding was also decreased by FK506, indicating that both IL-8 kappa B-like site and Ig kappa B site are FK506-sensitive in spite of the difference of binding factors. Our results indicate that not only the reported IL-2 NF-AT and NFIL-2A sites and Ig kappa B site, but also the IL-8 AP-1 and kappa B-like sites are terminals of FK506-sensitive pathway involving Ca2+ mobilization.

kappa B-like

kappa B-like

JunD

c-Fos

c-Rel

Ig kappa B

NF-AT

Ig kappa B

recognized

c-Fos

suppressed

transcription

suppressed

induced

suppressed

induced

through

transcription

induced

through

induced

through

targets

targets

kappa B-like

terminals

terminals

kappa B-like

transcription

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:
Monocyte tethering by P-selectin regulates monocyte chemotactic protein-1 and tumor necrosis factor-alpha secretion. Signal integration and NF-kappa B translocation [see comments]
Adhesion molecules that tether circulating leukocytes to endothelial cells may also transduce or modulate outside-in signals for cellular activation, providing an initial regulatory point in the inflammatory response. Adhesion of human monocytes to P-selectin, the most rapidly expressed endothelial tethering factor, increased the secretion of monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) by the leukocytes when they were stimulated with platelet-activating factor. Increased cytokine secretion was specifically inhibited by G1, an anti-P-selectin mAb that prevents P-selectin from binding to its ligand (P-selectin glycoprotein ligand-1) on myeloid cells. Moreover, tethering by P-selectin specifically enhanced nuclear translocation of nuclear factor-kappa B (NF-kappa B), a transcription factor required for expression of MCP-1, TNF-alpha, and other immediate-early genes. These results demonstrate that P-selectin, through its ligands on monocytes, may locally regulate cytokine secretion in inflamed tissues.

P-selectin

monocyte chemotactic protein-1

tumor necrosis factor-alpha

P-selectin

monocyte chemotactic protein-1

tumor necrosis factor-alpha

TNF-alpha

P-selectin

P-selectin

P-selectin glycoprotein ligand-1

P-selectin

TNF-alpha

P-selectin

binding

P-selectin

P-selectin glycoprotein ligand-1

expressed

P-selectin

expression

expression

TNF-alpha

secretion

monocyte chemotactic protein-1

secretion

tumor necrosis factor-alpha

secretion

secretion

TNF-alpha

prevents

binding

increased

secretion

when

secretion

required

expression

regulates

secretion

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:
HMG-I binds to GATA motifs: implications for an HPFH syndrome.
We have examined binding of the nuclear protein HMG-I to the human gamma-globin promoter. We find that HMG-I binds preferentially to the more 3' of a pair of GATA motifs in the gamma-globin promoter; this paired motif is bound by the erythroid factor GATA-1. A naturally occurring mutation (-175 T-C) in the area bound by HMG-I results in overexpression of gamma-globin in adult red blood cells (HPFH) and up-regulation of the gamma-globin promoter in in vitro expression assays; HMG-I does not bind to this mutant sequence. A survey of GATA motifs from other globin cis-elements demonstrates HMG-I binding to most of them. These findings implicate HMG-I in the HPFH phenotype; we speculate that it may participate in the formation of multiprotein complexes that regulate globin gene expression.

HMG-I

HMG-I

HMG-I

HMG-I

HMG-I

HMG-I

HMG-I

binds

HMG-I

binding

HMG-I

binds

HMG-I

bound

bound

HMG-I

bind

HMG-I

binding

HMG-I

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:
Positive and negative regulation of granulocyte-macrophage colony-stimulating factor promoter activity by AML1-related transcription factor, PEBP2.
The granulocyte-macrophage colony-stimulating factor (GM-CSF) gene promoter contains a consensus sequence for the polyomavirus enhancer binding-protein 2 (PEBP2) transcription factor, which consists of alpha and beta subunits. There are at least two genes, alpha A and alpha B, encoding the alpha subunit. alpha B is the mouse homologue of human AML1 gene detected at the breakpoints of t(8;21) and t(3;21) myeloid leukemias. We examined alpha A1 (an alpha A-gene product) and alpha B1 and alpha B2 (two alpha B-encoded isomers) for their effects on the GM-CSF promoter. PEBP2 alpha A1, alpha B1, and alpha B2 proteins bound the PEBP2 site within the mouse GM-CSF promoter. PEBP2 alpha A1 and alpha B1 enhanced the expression of the GM-CSF promoter-driven reporter plasmid in unstimulated and 12-O-tetradecanoylphorbol 13-acetate/phytohemagglutinin-stimulated human Jurkat T cells. In contrast, the promoter activity was suppressed by alpha B2. Coexpression of alpha B1 and alpha B2 showed that the promoter activity could be determined by the alpha B1/alpha B2 ratio. Jurkat cell extract contained PEBP2 site-binding protein(s) that cross-reacted with antimouse alpha A1 antibodies. Northern blot analysis indicated the expression of human PEBP2 alpha A, alpha B (AML1), and beta genes in Jurkat cells. Although further studies are required to determine the precise role of PEBP2 in the GM-CSF promoter activity, the present findings suggested the importance of the relative ratio of different PEBP2 isoforms in regulating the levels of the promoter activity.

promoter

promoter

PEBP2 site

promoter

promoter

granulocyte-macrophage colony-stimulating factor

granulocyte-macrophage colony-stimulating factor

GM-CSF

alpha A1

alpha B1

alpha B2

GM-CSF

PEBP2 alpha A1

alpha B1

alpha B2

GM-CSF

PEBP2 alpha A1

alpha B1

GM-CSF

phytohemagglutinin

alpha B2

alpha B1

alpha B2

alpha B1

alpha B2

alpha A1

GM-CSF

bound

PEBP2 alpha A1

PEBP2 site

GM-CSF

bound

alpha B1

PEBP2 site

GM-CSF

bound

alpha B2

PEBP2 site

GM-CSF

Coexpression

alpha B1

Coexpression

alpha B2

expression

negative regulation

granulocyte-macrophage colony-stimulating factor

promoter

suppressed

GM-CSF

promoter

alpha B2

regulation

granulocyte-macrophage colony-stimulating factor

promoter

effects

alpha A1

GM-CSF

promoter

effects

alpha B1

GM-CSF

promoter

effects

alpha B2

GM-CSF

promoter

determined

GM-CSF

promoter

alpha B1

determined

GM-CSF

promoter

alpha B2

role

GM-CSF

promoter

importance

regulating

regulating

GM-CSF

promoter

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:
Differential induction of the NF-AT complex during restimulation and the induction of T-cell anergy.
Stimulation of human CD4+ T-cell clones through the T-cell receptor (TcR) by high doses of specific peptide results in the induction of a long-lived state of nonresponsiveness that has been called anergy. During the induction of anergy, T cells are phenotypically similar to cells responding to an immunogenic stimulus. The amount of TcR at the cell surface is downmodulated, whereas the CD2 and CD25 receptors are increased. When restimulated, however, anergic T cells fail to up-regulate transcription of the IL-2 gene and in consequence do not produce IL-2. In this study, we have compared the ability of various transcription factors to bind to their appropriate site on DNA. Factors were isolated from the nuclei of T cells that were in the induction phase of anergy or were undergoing activation. The pattern of binding activity in restimulated T cells is consistent with the pattern that has previously been shown to regulate T-cell-specific expression of the IL-2 and the beta chain of the TcR genes. The measured binding to a TCF-1 site is the same in the nuclei of resting, activated, and anergized cells. The inducible factors NK-kappa B, beta E2, CD28RC, and AP-1 are not expressed in resting cells and are twofold lower in anergized as compared with activated cells. In contrast, anergic T cells express approximately eightfold lower amounts of NF-AT, a member of the class of inducible factors that regulates IL-2 gene transcription. (ABSTRACT TRUNCATED AT 250 WORDS)

binding

produce

expression

expressed

up-regulate

transcription

in consequence

up-regulate

produce

regulate

expression

regulates

transcription

transcription

transcription

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 retinoblastoma gene product negatively regulates transcriptional activation mediated by the human cytomegalovirus IE2 protein.
The IE2 gene product of human cytomegalovirus (HCMV) is one of a few viral regulatory proteins expressed immediately upon infection of the host cell. It is a potent transcriptional activator of many viral and cellular promoters. We found that the retinoblastoma susceptibility gene product (Rb) dramatically suppressed this IE2 transactivation of various promoters. However, unlike another tumor suppressor protein, p53, Rb did not have any significant effect on basal levels of transcription, suggesting that Rb specifically interacts with IE2 rather than other cellular factors involved in the general transcription machinery. We found by protein-affinity chromatography that Rb in nuclear extracts or produced by in vitro translation directly bound to IE2. Our results suggest that Rb may regulate the life cycle of HCMV, which is endemic in the human population. Furthermore, these data may provide new insights into the slow rate of HCMV DNA replication in cells and the possible involvement of HCMV in tumorigenesis.

Rb

Rb

Rb

Rb

Rb

interacts

Rb

bound

Rb

expressed

upon

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:
Epstein-Barr virus replicative gene transcription during de novo infection of human thymocytes: simultaneous early expression of BZLF-1 and its repressor RAZ.
Epstein-Barr virus (EBV) is known to infect B cells and epithelial cells. We and others have shown that EBV can also infect a subset of thymocytes. Infection of thymocytes was accompanied by the appearance of linear EBV genome within 8 hr of infection. Circularization of the EBV genome was not detected. This is in contrast to the infection in B cells where the genome can circularize within 24 hr of infection. The appearance of the BamHI ZLF-1 gene product, ZEBRA, by RT-PCR, was observed within 8 hr of infection. The appearance of a novel fusion transcript (RAZ), which comprised regions of the BZLF-1 locus and the adjacent BRLF-1 locus, was detected by RT-PCR. ZEBRA protein was also identified in infected thymocytes by immunoprecipitation. In addition, we demonstrated that the EBNA-1 gene in infected thymocytes was transcribed from the Fp promoter, rather than from the Cp/Wp promoter which is used in latently infected B cells. Transcripts encoding gp350/220, the major coat protein of EBV, were identified, but we did not find any evidence of transcription from the LMP-2A or EBER-1 loci in infected thymocytes. These observations suggest that de novo EBV infection of thymocytes differs from infection of B cells. The main difference is that with thymocytes, no evidence could be found that the virus ever circularizes. Rather, EBV remains in a linear configuration from which replicative genes are transcribed.

RAZ

BamHI ZLF-1

ZEBRA

RAZ

ZEBRA

expression

expression

RAZ

appearance

ZEBRA

appearance

RAZ

identified

ZEBRA

from

transcribed

rather than

transcribed

transcribed

Transcripts

transcription

transcription

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 Sp1 phosphorylation and NF-kappa B-independent HIV promoter domain activity in T lymphocytes stimulated by okadaic acid.
In contrast to the purely enhancer-dependent effect of cytokines such as TNF on the activity of the HIV regulatory region (LTR), we observed that okadaic acid (OKA) activates HIV transcription through both the enhancer, responding to the factor NF-kappa B, and the promoter domain of the LTR. The inducibility of HIV LTR-driven luciferase expression constructs in lymphoblastoid cells stimulated by OKA depended on both functional Sp1 binding elements and the ability of the TATA box to bind the protein TBP. In both transformed and normal lymphocytes, OKA stimulation induced intense phosphorylation of the constitutively expressed Sp1 protein in the nucleus, a property of OKA not shared by TNF, phorbol ester, or PHA and interleukin 2. Responsiveness of LTR constructs deleted of kappa B elements to HIV Tat expression was increased upon OKA but not TNF stimulation. Our results suggest that SP1 phosphorylation induced by OKA, a selective inhibitor of the serine-threonine phosphatase PP2A, facilitates the formation of a transcription complex involving general transcription factors, HIV Tat, and Sp1 proteins. The formation of this complex would increase, independently of an in synergy with NF-kappa B, the low basal activity of the HIV LTR observed in normal T lymphocytes.

PHA

interleukin 2

Tat

Tat

complex

Tat

expression

Tat

phosphorylation

phosphorylation

phosphorylation

Induction

phosphorylation

induced

phosphorylation

induced

phosphorylation

facilitates

induced

complex

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:
Human MHC class II gene transcription directed by the carboxyl terminus of CIITA, one of the defective genes in type II MHC combined immune deficiency.
Type II major histocompatibility complex combined immune deficiency (type II MHC CID or bare lymphocyte syndrome) is a congenital immunodeficiency disease characterized by absent MHC class II expression. Four distinct complementation groups have been identified. Recently, the defective gene in group II type II MHC CID has been isolated and termed CIITA. Here, we demonstrate that CIITA is an MHC class II gene-specific transcription activator. The transcription activation function is provided by the N-terminal acidic domain (amino acids 26-137), which is experimentally exchangeable with a heterologous viral transcription-activating domain. The specificity of CIITA for three major MHC class II genes, DR, DQ and DP, is mediated by its remaining C-terminal residues (amino acids 317-1130). The transactivation of multiple cis elements, especially S and X2, of the DR alpha proximal promoter in group II CID cells is CIITA dependent. Since CIITA overexpression in normal cells did not increase class II expression, we propose that initiation of CIITA expression serves as the on-off switch, while availability of downstream interactor(s) limits transcription.

S

CIITA

CIITA

CIITA

CIITA

DR alpha

CIITA

CIITA

CIITA

overexpression

CIITA

expression

CIITA

transactivation

S

DR alpha

transactivation

DR alpha

overexpression

overexpression

initiation

expression

dependent

transactivation

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:
Abnormal regulation of the IL-2 promoter in lpr CD4-CD8- T lymphocytes results in constitutive expression of a novel nuclear factor of activated T cells-binding factor.
The inert quality of MRL-Ipr/Ipr (Ipr) peripheral CD4-CD8- (CD4-8-) T cells manifests primarily as an inability to proliferate or produce IL-2 in response to TCR or mitogenic stimulation. Yet these same cells do initiate early TCR-mediated signaling events, such as generation of inositol phosphates and increased intracellular calcium. They also display constitutively high levels of p59fyn and CD3 zeta tyrosine phosphorylation. The generation of second messengers in T cells normally leads to downstream signaling that results in transcriptional activation of the IL-2 gene. We, therefore, compared the activation state of the IL-2 gene promoter region in freshly isolated and stimulated Ipr CD4-8- T cells with that of normal T lymphocytes. Levels of the octamer, NF-kappa B (p50-p65 heterodimer), and AP-1 transcriptional factors are constitutively elevated in freshly isolated Ipr CD4-8- T cells, consistent with the activated phenotype of these cells. Upon stimulation with mitogens, formation of the transactivating complex, nuclear factor of activated T cells (NF-AT), occurs with normal kinetics in Ipr CD4-8- T cells. Yet, the levels of the activating NF-AT complex never reach those observed in similarly stimulated normal T cells. Furthermore, nuclear extracts from Ipr CD4-8- T cells display high levels of a novel specific binding activity at the NF-AT site, which is present at much lower levels in freshly isolated normal T lymphocytes. Upon mitogenic stimulation, the binding activity of the novel NF-AT-binding factor is rapidly down-regulated in normal T cells, but persists at high levels in Ipr CD4-8- T cells. These two abnormalities at the NF-AT site provide a potential mechanism to account for the defect in IL-2 production from Ipr CD4-8- T cells.

promoter

tyrosine

CD3 zeta

produce

production

defect

production

phosphorylation

tyrosine

phosphorylation

CD3 zeta

tyrosine

inability

produce

high levels

phosphorylation

results

transcriptional activation

transcriptional activation

activation

account

production

Abnormal regulation

promoter

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.