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)

Breast cancer susceptibility gene BRCA1 has been implicated in the control of gene regulation and such regulated genes are thought to mediate the biological role of BRCA1. Overexpression of BRCA1 induces GADD45, a p53-regulated and stress-inducible gene. However, the molecular mechanism by which BRCA1 induces the expression GADD45 remains unclear. In this report, we have shown that the GADD45 promoter is strongly activated following expression of wild-type BRCA1. In contrast, both the tumor-derived BRCA1 mutants (p1749R and Y1853insA) and truncated BRCA1 mutant protein (Delta500 - 1863 BRCA1), which lack transactivation activity, were unable to activate the GADD45 promoter, indicating that the BRCA1-mediated activation of the GADD45 promoter requires normal transcriptional properties of BRCA1. BRCA1 did not induce the c-Jun and c-fos promoters, which rules out a general effect of BRCA1 on other immediate-responsive genes. Expression of the human papillomavirus E6 and the dominant-negative mutant p53 proteins had no effect on the induction of the GADD45 promoter by BRCA1, suggesting that activation of the GADD45 promoter by BRCA1 is independent of cellular p53 function. With the 5'-deletion analysis, the BRCA1-responsive element of the GADD45 promoter was mapped at the region from -121 to -75. Disruption of this region resulted in the abrogation of BRCA1 activation of the GADD45 promoter. Taken together, these results demonstrate that the mechanism by which BRCA1 induces GADD45 is mainly through the transactivation of the GADD45 promoter, further demonstrating the evidence that GADD45 acts as one of the BRCA1-regulated genes. Oncogene (2000) 19, 4050 - 4057.
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PMID:BRCA1 activation of the GADD45 promoter. 1096 62

We describe a novel nerve growth factor (NGF)-signaling pathway leading to gadd45 induction that is independent of JNK and p38 MAPK. We used cDNA arrays representing 588 genes to investigate the role of differential gene expression in NGF-mediated pleiotropic responses. We compared the gene expression profiles obtained from MED283-TrkA cells undergoing NGF-induced apoptosis to PC12 cells undergoing NGF-induced differentiation. An early and specific transcriptional target of NGF in MED283-TrkA cells was the DNA-damage-inducible gene gadd45. Its magnitude of induction directly correlated with the magnitude of apoptosis in MED283 clones transfected with mutant TrkA receptors. Although gadd45 has been implicated in stress response signaling, in vitro kinase assays indicated that NGF neither activated c-Jun NH2-terminal kinase (JNK) nor p38 mitogen-activated protein kinase (MAPK). Furthermore, the p38 MAPK inhibitor SB203580 (20 microM) failed to prevent NGF-induced apoptosis and NGF-induced gadd45 expression. These results suggest that differential regulation of gadd45 expression possibly through BRCA1 may be a potential mechanism whereby NGF regulates pleiotropic responses.
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PMID:p38 mitogen-activated protein kinase-independent induction of gadd45 expression in nerve growth factor-induced apoptosis in medulloblastomas. 1154 51

Gene expression is coordinated in part by interactions between transcriptional activators and other transcription factors such as coactivators. The KIX domain of the coactivator and histone acetyltransferase CREB binding protein (CBP) binds numerous mammalian and viral transcriptional activators such as BRCA1, CREB, c-Jun, c-Myb, p53, papillomavirus E2, and HTLV-1 Tax. Formation of the CREB-CBP complex depends on phosphorylation of the KID region of CREB and involves induced folding of KID upon binding a hydrophobic groove of the KIX domain of CBP. Here we investigate the formation of the complex formed by human KIX and the N-terminal activation domain of human c-Jun. The c-Jun activation domain and KID do not share significant sequence similarity. Circular dichroism spectroscopy shows that the Jun N-terminal activation domain is intrinsically disordered in isolation and that KIX binding is independent of Jun phosphorylation. In contrast to the mode of binding exhibited by CREB, NMR chemical shift mapping indicates that the c-Jun activation domain binds to a distinctly different surface of KIX than used by CREB. Moreover, NMR and sedimentation equilibrium studies show that the activation domains of c-Jun and CREB can simultaneously bind the KIX domain of CBP. The results illustrate a new mode of binding and combinatorial recruitment via the KIX domain of CBP by multiple transcriptional activators.
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PMID:Structurally distinct modes of recognition of the KIX domain of CBP by Jun and CREB. 1243 52

BRCA1 is a central component of the DNA damage response mechanism and defects in BRCA1 confer sensitivity to a broad range of DNA damaging agents. BRCA1 is required for homologous recombination and DNA damage-induced S and G(2)/M phase arrest. We show here that BRCA1 is required for ATM- and ATR-dependent phosphorylation of p53, c-Jun, Nbs1 and Chk2 following exposure to ionizing or ultraviolet radiation, respectively, and is also required for ATM phosphorylation of CtIP. In contrast, DNA damage-induced phosphorylation of the histone variant H2AX is independent of BRCA1. We also show that the presence of BRCA1 is dispensable for DNA damage-induced phosphorylation of Rad9, Hus1 and Rad17, and for the relocalization of Rad9 and Hus1. We propose that BRCA1 facilitates the ability of ATM and ATR to phosphorylate downstream substrates that directly influence cell cycle checkpoint arrest and apoptosis, but that BRCA1 is dispensable for the phosphorylation of DNA-associated ATM and ATR substrates.
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PMID:A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein. 1277

BRCA1 has been implicated in a number of cellular processes, including transcriptional regulation, DNA damage repair, cell cycle arrest, and apoptosis. We identified mitogen-activated protein kinase (MAPK) kinase kinase 3 (MEKK3), an upstream regulator of the c-Jun NH(2)-terminal kinase/stress-activated protein kinase and p38/MAPK pathways, as a novel BRCA1-interacting protein in a yeast two-hybrid screen and confirmed the interaction by coimmunoprecipitation in mammalian cells. Deletion mapping demonstrated that amino acids 1611-1863 are required to mediate the interaction with MEKK3 in yeast. BRCA1 disease-associated mutations abrogated the interaction in yeast, and BRCA1 failed to interact with MEKK3 in BRCA1 mutant HCC1937 breast cancer cells. We demonstrate that small interfering RNA-based inhibition of endogenous BRCA1 reduces MEKK3 kinase activity and conversely that inducible expression of BRCA1 activates MEKK3 and p38/MAPK. Finally, we demonstrate using complementary approaches that BRCA1 is required for paclitaxel-induced activation of MEKK3. These data indicate that BRCA1 is a key regulator of the paclitaxel-induced stress response pathway and suggest that the ability of BRCA1 to associate with, and mediate the activation of, MEKK3 represents a potential mechanism through which this pathway is regulated.
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PMID:BRCA1 interacts with and is required for paclitaxel-induced activation of mitogen-activated protein kinase kinase kinase 3. 1520 25

Mammary epithelial cells cultured on a concentrated laminin-rich extracellular matrix formed 3D acinar structures that matured to polarized monolayers surrounding a lumen. In the absence of glucocorticoids mature acinus formation failed and the expression of an acinus-associated, activator protein 1 (AP1) and nuclear factor kappaB transcription factor DNA-binding profile was lost. Treatment with the JNK inhibitor, SP600125, caused similar effects, whereas normal organization of the mammary epithelial cells as acini caused JNK activation in a glucocorticoid-dependent manner. The forming acini expressed BRCA1, GADD45beta, MEKK4, and the JNK activating complex GADD 45beta-MEKK4 in a glucocorticoid-dependent fashion. JNK catalyzed phosphorylation of c-Jun was also detected in the acini. In addition, expression of beta4 integrin and in situ occupation of its promoter by AP1 components, c-Jun and Fos, was glucocorticoid dependent. These results suggest that glucocortocoid signaling regulates acinar integrity through a pathway involving JNK regulation of AP1 transcription factors and beta4 integrin expression.
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PMID:Organization of mammary epithelial cells into 3D acinar structures requires glucocorticoid and JNK signaling. 1522 8

Mutations in the breast cancer susceptibility gene (BRCA1) account for a significant proportion of hereditary breast and ovarian cancers. Cofactor of BRCA1 (COBRA1) was isolated as a BRCA1-interacting protein and exhibited a similar chromatin reorganizing activity to that of BRCA1. However, the biological role of COBRA1 remains largely unexplored. Here, we report that ectopic expression of COBRA1 inhibited activator protein 1 (AP-1) transcriptional activity in transfected cells in a dose-dependent manner, whereas reduction of endogenous COBRA1 with a small interfering RNA significantly enhanced AP-1-mediated transcriptional activation. COBRA1 physically interacted with the AP-1 family members, c-Jun and c-Fos, and the middle region of COBRA1 bound to c-Fos. Lack of c-Fos binding site in the COBRA1 completely abolished the COBRA1 inhibition of AP-1 trans-activation. These findings suggest that COBRA1 may directly modulate AP-1 pathway and, therefore, may play important roles in cell proliferation, differentiation, apoptosis, and oncogenesis.
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PMID:COBRA1 inhibits AP-1 transcriptional activity in transfected cells. 1553 Apr 30

The regulator of cell cycle progression, cyclin D1, is up-regulated in breast cancer cells; its expression is, in part, dependent on ERalpha signaling. However, many ERalpha-negative tumors and tumor cell lines (e.g., SKBR3) also show over-expression of cyclin D1. This suggests that, in addition to ERalpha signaling, cyclin D1 expression is under the control of other signaling pathways; these pathways may even be over-expressed in the ERalpha-negative cells. We previously noticed that both ERalpha-positive and -negative cell lines over-express BRCA1-IRIS mRNA and protein. Furthermore, the level of over-expression of BRCA1-IRIS in ERalpha-negative cell lines even exceeded its over-expression level in ERalpha-positive cell lines. In this study, we show that: (1) BRCA1-IRIS forms complex with two of the nuclear receptor co-activators, namely, SRC1 and SRC3 (AIB1) in an ERalpha-independent manner. (2) BRCA1-IRIS alone, or in connection with co-activators, is recruited to the cyclin D1 promoter through its binding to c-Jun/AP1 complex; this binding activates the cyclin D1 expression. (3) Over-expression of BRCA1-IRIS in breast cells over-activates JNK/c-Jun; this leads to the induction of cyclin D1 expression and cellular proliferation. (4) BRCA1-IRIS activation of JNK/c-Jun/AP1 appears to account for this, because in cells that were depleted from BRCA1-IRIS, JNK remained inactive. However, depletion of SRC1 or SRC3 instead reduced c-Jun expression. Our data suggest that this novel signaling pathway links BRCA1-IRIS to cellular proliferation through c-Jun/AP1 nuclear pathway; finally, this culminates in the increased expression of the cyclin D1 gene.
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PMID:BRCA1-IRIS regulates cyclin D1 expression in breast cancer cells. 1686 Mar 16

The Gadd45 family of proteins is known to play a central role as cellular stress sensors that modulate the response of mammalian cells to stress inflicted by physiologic and environmental stressors. Gadd45a was shown to be a direct target to the p53 and BRCA1 tumor suppressor genes, whose loss of function is known to play a vital role in breast carcinogenesis; however, the role of Gadd45a in the suppression of breast cancer remains unclear. To address this issue, Gadd45a-deficient mice were crossed with breast cancer prone mouse mammary tumor virus-Ras mice to generate mice that express activated Ras and differ in their Gadd45a status. Using this mouse model, we show that the loss of Gadd45a accelerates Ras-driven mammary tumor formation, exhibiting increased growth rates and a more aggressive histologic phenotype. Moreover, it is shown that accelerated Ras-driven tumor formation in the absence of Gadd45a results in both a decrease in apoptosis, which is linked to a decrease in c-Jun NH(2)-terminal kinase (JNK) activation, and a decrease in Ras-induced senescence, which is correlated with a decrease in p38 kinase activation. Altogether, these results provide a novel model for the tumor-suppressive function of Gadd45a in the context of Ras-driven breast carcinogenesis, showing that Gadd45a elicits its function through activation of the stress-induced JNK and p38 kinases, which contribute to increase in apoptosis and Ras-induced senescence.
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PMID:Gadd45a suppresses Ras-driven mammary tumorigenesis by activation of c-Jun NH2-terminal kinase and p38 stress signaling resulting in apoptosis and senescence. 1695 Nov 55

Cyclin D1 plays an important role in cell cycle progression. In breast cancer, Cyclin D1 expression is deregulated by several mechanisms. We previously showed that in breast cancer cells, overexpression of BRCA1-IRIS induces Cyclin D1 overexpression and increases cell proliferation. BRCA1-IRIS alone or in complex with steroid receptor co-activators was targeted to the cyclin D1 promoter pre-bound by the c-Jun/AP1 and activated its transcription, which could explain the co-overexpression of BRCA1-IRIS and Cyclin D1 in breast cancer cells coupled with their increased proliferation. We report here an alternate or a complementary pathway by which BRCA1-IRIS activates Cyclin D1 expression. BRCA1-IRIS overexpression decreases the expression of the dual specificity phosphatase, DUSP3/VHR, an endogenous inhibitor of several MAPKs, including c-Jun N-terminal kinase. Although, the mechanism by which BRCA1-IRIS overexpression accomplishes that is not yet known, it is sufficient to induce Cyclin D1 overexpression in a human mammary epithelial cell model. Cyclin D1 overexpression could be blocked by co-overexpression of VHR in those cells. Furthermore, in 2 breast cancer cell lines that overexpress both BRCA1-IRIS and Cyclin D1 (MCF-7 and SKBR3) depletion of BRCA1-IRIS by RNA interference attenuated the expression of Cyclin D1 by elevating the expression level of VHR. These data demonstrate a critical role for BRCA1-IRIS in human breast cancer cell-cycle control and suggest that deregulated expression of BRCA1-IRIS is likely to reduce dependence on normal physiological growth stimuli, thereby providing a growth advantage to tumor cells and a potential mechanism of resistance to endocrine therapy.
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PMID:BRCA1-IRIS activates cyclin D1 expression in breast cancer cells by downregulating the JNK phosphatase DUSP3/VHR. 1727 98


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