Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The CREB-binding protein (CBP) plays a central role in the regulation of gene expression by several different second messenger pathways including serum growth factors, cAMP and phorbol esters. CBP specifically binds to the phosphorylated forms of CREB and c-Jun and is thought to activate transcription through a C-terminal activation domain. In this report, we demonstrate that the C terminus of CBP is dispensable for its ability to stimulate phospho-CREB activity, and, further, that the deletion of this domain produces highly active, mutant forms of CBP. The novel N-terminal activation identified by this deletional analysis consists of the first 714 amino acids of CBP and is sufficient for high levels of transcriptional activity. This domain is also capable of stimulating the activity of a second cAMP-regulated factor, ATF-1. Surprisingly, ATF-1 activity is not significantly stimulated by full-length CBP suggesting that the C-terminal domain of CBP may also serve to regulate ATF-1/CBP activity. Additionally, the demonstration that one of our hyperactive CBP mutants is able to activate a nonphosphorylatable mutant of CREB (M1 CREB) provides the first evidence that CBP may play a role in regulating the basal transcriptional activity of CREB.
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PMID:Identification and characterization of a novel transcriptional activation domain in the CREB-binding protein. 866 3

CREB-binding protein (CBP) functions as a coactivator molecule for a number of transcription factors including CREB, c-Fos, c-Jun, c-Myb, and several nuclear receptors. Although binding sites for these factors within CBP have been identified, the regions of CBP responsible for transcriptional activation are unknown. In this report, we show that the N-terminal half of CBP is sufficient for activation of CREB-mediated transcription and that this region contains a strong transcriptional activation domain (TAD). Both deletion of this TAD or sequestering of factors that the TAD binds using a squelching assay were found to greatly decrease the ability of CBP to activate CREB-mediated transcription. In vivo studies by others have shown that p300/CBP associates with TBP; using an in vitro approach, we show the N-terminal TAD binds TBP. We also examined the ability of the C terminus of CBP to activate transcription using GAL-CBP chimeras. With this approach, we identified two C-terminal TADs located adjacent to the c-Fos binding site. In previous studies, cAMP-dependent protein kinase A (PKA) increased the transcriptional activity of a GAL full-length CBP chimera in F9 cells, and of the C terminus in PC-12 cells. Here, we demonstrate that PKA also increased the ability of the N-terminal TADs of CBP to activate transcription in PC-12 but not F9 or COS-7 cells, suggesting that this PKA-responsiveness is cell type-specific.
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PMID:CREB-binding protein activates transcription through multiple domains. 891 Apr 28

Smad proteins have recently been identified as mediators of transcriptional activation by members of the transforming growth factor-beta superfamily. To determine if Smads might also be involved in inducing gene transcription in response to other agonists, expression vectors for dominant-negative Smad proteins were constructed. These plasmids were transiently cotransfected with luciferase reporter genes and the effects of various agonists on reporter gene activity evaluated in NIH 3T3 cells. Dominant-negative Smad3, but not other dominant-negative Smads, reduced stimulation of the plasminogen activator inhibitor-1 (PAI-1) and other gene promoters by phorbol ester, cAMP, and platelet-derived growth factor. Activation of the PAI-1 promoter by TGF-beta or prostaglandin F2 alpha, and transactivation by c-Jun or JunB were not inhibited by dominant-negative Smad3, supporting the specificity of this mutant. These results suggest that Smad3, like CREB-binding protein (CBP), may participate in transcriptional activation by multiple agonists.
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PMID:Dominant-negative SMAD-3 interferes with transcriptional activation by multiple agonists. 912 13

The activity of c-Jun, the major component of the transcription factor AP-1, is potentiated by amino-terminal phosphorylation on serines 63 and 73 (Ser-63/73). This phosphorylation is mediated by the Jun amino-terminal kinase (JNK) and required to recruit the transcriptional coactivator CREB-binding protein (CBP). AP-1 function is antagonized by activated members of the steroid/thyroid hormone receptor superfamily. Recently, a competition for CBP has been proposed as a mechanism for this antagonism. Here we present evidence that hormone-activated nuclear receptors prevent c-Jun phosphorylation on Ser-63/73 and, consequently, AP-1 activation, by blocking the induction of the JNK signaling cascade. Consistently, nuclear receptors also antagonize other JNK-activated transcription factors such as Elk-1 and ATF-2. Interference with the JNK signaling pathway represents a novel mechanism by which nuclear hormone receptors antagonize AP-1. This mechanism is based on the blockade of the AP-1 activation step, which is a requisite to interact with CBP. In addition to acting directly on gene transcription, regulation of the JNK cascade activity constitutes an alternative mode whereby steroids and retinoids may control cell fate and conduct their pharmacological actions as immunosupressive, anti-inflammatory, and antineoplastic agents.
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PMID:Nuclear hormone receptor antagonism with AP-1 by inhibition of the JNK pathway. 940 28

The involvement of serine/threonine protein phosphatases in signaling pathways that control the expression of the cyclooxygenase-2 (COX-2) gene in human chondrocytes was examined. Okadaic acid (OKA), an inhibitor of protein phosphatases 1 (PP-1) and 2A (PP-2A), induced a delayed, time-dependent increase in the rate of COX-2 gene transcription (runoff assay) resulting in increased steady-state mRNA levels and enzyme synthesis. The latter response was dose dependent over a narrow range of 1-30 nmol/L with declining expression and synthesis of COX-2 at higher concentrations due to cell toxicity. The delayed increase in COX-2 mRNA expression was accompanied by the induction of the proto-oncogenes c-jun, junB, junD, and c-fos (but not FosB or Fra-1). Increased phosphorylation of CREB-1/ATF-1 transcription factors was observed beginning at 4 h and reached a zenith at 8 h. Gel-shift analysis confirmed the up-regulation of AP-1 and CRE nuclear binding proteins, though there was little or no OKA-induced nuclear protein binding to SP-1, AP-2, NF-kappaB or NF-IL-6 regulatory elements. OKA-induced nuclear protein binding to 32P-CRE oligonucleotides was abrogated by a pharmacological inhibitor of protein kinase A (PKA), KT-5720; the latter compound also inhibited OKA-induced COX-2 enzyme synthesis. Calphostin C (CalC), an inhibitor of PKC isoenzymes, had little effect in this regard. Inhibition of 12P-CRE binding was also observed in the presence of an antibody to CREB-binding protein (265-kDa CBP), an integrator and coactivator of cAMP-responsive genes. The binding to 32P-CRE was unaffected in the presence of excess radioinert AP-1 and COX-2 NF-IL-6 oligonucleotides, although a COX-2 CRE-oligo competed very efficiently. 32P-AP-1 consensus sequence binding was unaffected by incubation of chondrocytes with KT-5720 or CalC, but was dramatically diminished by excess radioinert AP-1 and CRE-COX-2 oligos. Supershift analysis in the presence of antibodies to c-Jun, c-Fos, JunD, and JunB suggested that AP-1 complexes were composed of c-Fos, JunB, and possibly c-Jun. OKA has no effect on total cellular PKC activity but caused a delayed time-dependent increase in total PKA activity and synthesis. OKA suppressed the activity of the MAP kinases, ERK1/2 in a time-dependent fashion, suggesting that the Raf-1/MEKK1/MEK1/ERK1,2 cascade was compromised by OKA treatment. By contrast, OKA caused a dramatic increase in SAPK/JNK expression and activity, indicative of an activation of MEKK1/JNKK/SAPK/JNK pathway. OKA stimulated a dose-dependent activation of CAT activity using transfected promoter-CAT constructs harboring the regulatory elements AP-1 (c-jun promoter) and CRE (CRE-tkCAT). We conclude that in primary phenotypically stable human chondrocytes, COX-2 gene expression may be controlled by critical phosphatases that interact with phosphorylation dependent (e.g., MAP kinases:AP-1, PKA:CREB/ATF) signaling pathways. AP-1 and CREB/ATF families of transcription factors may be important substrates for PP-1/PP-2A in human chondrocytes.
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PMID:Transcriptional induction of cyclooxygenase-2 gene by okadaic acid inhibition of phosphatase activity in human chondrocytes: co-stimulation of AP-1 and CRE nuclear binding proteins. 962 Jan 67

Calcium is the principal second messenger in the control of gene expression by electrical activity in neurons. Recruitment of the coactivator CREB-binding protein, CBP, by the prototypical calcium-responsive transcription factor, CREB and stimulation of CBP activity by nuclear calcium signals is one mechanism through which calcium influx into excitable cells activates gene expression. Here we show that another CBP-interacting transcription factor, c-Jun, can mediate transcriptional activation upon activation of L-type voltage-gated calcium channels. Calcium-activated transcription mediated by c-Jun functions in the absence of stimulation of the c-Jun N-terminal protein kinase (JNK/SAPK1) signalling pathway and does not require c-Jun amino acid residues Ser63 and Ser73, the two major phosphorylation sites that regulate c-Jun activity in response to stress signals. Similar to CREB-mediated transcription, activation of c-Jun-mediated transcription by calcium signals requires calcium/ calmodulin-dependent protein kinases and is dependent on CBP function. These results identify c-Jun as a calcium-regulated transcriptional activator and suggest that control of coactivator function (i.e. recruitment of CBP and stimulation of CBP activity) is a general mechanism for gene regulation by calcium signals.
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PMID:c-Jun functions as a calcium-regulated transcriptional activator in the absence of JNK/SAPK1 activation. 1006 99

CREB-binding protein (CBP) and the closely related adenovirus E1A-associated 300-kD protein (p300) function as coactivators of transcription factors such as CREB, c-Fos, c-Jun, c-Myb, and several nuclear receptors. To study the roles of CBP in embryonic development, we generated CBP homozygous mutant mouse embryos that expressed a truncated form of CBP protein (1-1084 out of 2441 residues). The embryos died between embryonic days 9.5 (E9.5) and E10.5 and exhibited a defect in neural tube closure. They appeared pale and showed decreases in erythroid cells and colony-forming cells (CFCs) in the yolk sac, suggesting defects in primitive hematopoiesis. Immunohistochemistry with an anti-PECAM antibody showed a lack of vascular network formation. Organ culture of para-aortic splanchnopleural mesoderm (P-Sp) with stromal cells (OP9) showed an autonomous abnormality of putative endothelial precursors, which may induce the microenvironmental defect in hematopoiesis. In addition, these defects were partially rescued by the addition of VEGF to this culture. Our analyses demonstrate that CBP plays an essential role in hematopoiesis and vasculo-angiogenesis.
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PMID:Mice homozygous for a truncated form of CREB-binding protein exhibit defects in hematopoiesis and vasculo-angiogenesis. 1021 70

Bcl3, an IkappaB protein, was originally isolated as a putative proto-oncogene in a subset of B cell chronic lymphocytic leukemias. Bcl3 was subsequently shown to associate tightly with and transactivate the NFkappaB p50 or p52 homodimer. Herein, we show that Bcl3 stimulates the activating protein-1 (AP-1) transactivation, either alone or in conjunction with transcription integrators steroid receptor coactivator-1 and CREB-binding protein/p300. The C-terminal 158 residues of Bcl3 exhibited an autonomous transactivation function and interacted with specific subregions of the AP-1 components c-Jun and c-Fos, CREB-binding protein/p300, and steroid receptor coactivator-1, as demonstrated by the yeast and mammalian two-hybrid tests as well as glutathione S-transferase pull-down assays. In addition, anti-HA antibody co-precipitated c-Jun from HeLa cells co-expressing c-Jun and HA-tagged Bcl3, consistent with the idea that Bcl3 directly associates with AP-1 in vivo. Furthermore, microinjection of Bcl3 expression vector into Rat-1 fibroblast cells significantly enhanced DNA synthesis and expression of c-jun, one of the cellular target genes of AP-1. These results suggest that Bcl3 may directly participate in the tumorigenesis processes as a novel transcription coactivator of the mitogenic transcription factor AP-1 in vivo.
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PMID:Bcl3, an IkappaB protein, stimulates activating protein-1 transactivation and cellular proliferation. 1049 12

The adenovirus E1A protein interferes with regulators of apoptosis and growth by physically interacting with cell cycle regulatory proteins including the retinoblastoma tumor suppressor protein and the coactivator proteins p300/CBP (where CBP is the CREB-binding protein). The p300/CBP proteins occupy a pivotal role in regulating mitogenic signaling and apoptosis. The mechanisms by which cell cycle control genes are directly regulated by p300 remain to be determined. The cyclin D1 gene, which is overexpressed in many different tumor types, encodes a regulatory subunit of a holoenzyme that phosphorylates and inactivates PRB. In the present study E1A12S inhibited the cyclin D1 promoter via the amino-terminal p300/CBP binding domain in human choriocarcinoma JEG-3 cells. p300 induced cyclin D1 protein abundance, and p300, but not CBP, induced the cyclin D1 promoter. cyclin D1 or p300 overexpression inhibited apoptosis in JEG-3 cells. The CH3 region of p300, which was required for induction of cyclin D1, was also required for the inhibition of apoptosis. p300 activated the cyclin D1 promoter through an activator protein-1 (AP-1) site at -954 and was identified within a DNA-bound complex with c-Jun at the AP-1 site. Apoptosis rates of embryonic fibroblasts derived from mice homozygously deleted of the cyclin D1 gene (cyclin D1(-/-)) were increased compared with wild type control on several distinct matrices. p300 inhibited apoptosis in cyclin D1(+/+) fibroblasts but increased apoptosis in cyclin D1(-/-) cells. The anti-apoptotic function of cyclin D1, demonstrated by sub-G(1) analysis and annexin V staining, may contribute to its cellular transforming and cooperative oncogenic properties.
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PMID:Activation of the cyclin D1 gene by the E1A-associated protein p300 through AP-1 inhibits cellular apoptosis. 1056 90

Transforming growth factor-beta (TGFbeta) enhances transcription from reporter genes regulated by a single consensus cAMP-response element (CRE) upon transfection into the immortalized human keratinocyte cell line, HaCaT. Whereas both CRE-binding protein (CREB) and c-Jun present in extracts of unstimulated cells can complex with a CRE in gel-shift experiments, TGFbeta treatment increases the amount of c-Jun found in the complex. Overexpression of c-Jun is sufficient to increase CRE and GAL4-CREB-dependent transcription and mimics the stimulatory effects of TGFbeta on transcription from either reporter gene. Surprisingly, although a portion of CREB in unstimulated cells is phosphorylated on the activating serine residue, Ser-133, this level of phospho-CREB is not altered by TGFbeta treatment. In fact, the CREB-dependent transcriptional effects of TGFbeta or c-Jun do not require phosphorylation of Ser-133, although CREB-binding protein (CBP) is required as evidenced by the observation that the adenoviral oncoprotein E1A can block the effects of both agents. c-Jun enhancement of CRE or GAL4-CREB-dependent transcription neither requires the DNA-binding nor N-terminal domains of c-Jun. Collectively, these results are consistent with a model in which signaling pathways initiated by TGFbeta can stimulate CREB-dependent transcription by increasing the cellular concentration of c-Jun, which participates in activation of the CBP-containing transcription complex.
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PMID:c-Jun enhancement of cyclic adenosine 3',5'-monophosphate response element-dependent transcription induced by transforming growth factor-beta is independent of c-Jun binding to DNA. 1059 80


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