UNIPROT:P05412 - FACTA Search

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Query: UNIPROT:P05412 (c-Jun)
11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both epidemiological and experimental studies indicate that ethanol is a tumor promoter and may promote metastasis of breast cancer. However, the molecular mechanisms underlying ethanol-mediated tumor promotion remain unknown. Overexpression of ErbB proteins in breast cancer patients is generally associated with poor prognosis. The ErbB proteins are a family of receptor kinases that include four closely related members: epidermal growth factor receptor (EGFR/ErbB1), ErbB2/neu, ErbB3, and ErbB4. Particularly, ErbB2 plays a pivotal role in ErbB-mediated activities. Here we demonstrated that amplification of ErbB2 expression sensitized a specific cellular response to ethanol. Human breast cancer cells or mammary epithelial cells with a high expression of ErbB2 exhibited an enhanced response to ethanol-stimulated cell invasion in vitro. Ethanol also stimulated cell proliferation; however, this stimulation was independent of ErbB2 levels. Ethanol triggered divergent intracellular signaling among cells expressing different ErbB2 levels. In the cells overexpressing ErbB2, ethanol was more effective in the activation of c-Jun NH2 terminal protein kinases (JNKs) and p38 mitogen-activated protein kinase (p38 MAPK) as well as the induction of reactive oxygen species (ROS) than the cells with normal ErbB2 expression. Blockage of either JNKs or p38 MAPK activation eliminated ethanol-mediated cell invasion. In contrast, the reduction of hydrogen peroxide concentration by catalase exposure had little effect on ethanol-induced cell invasion. These results indicated that ethanol-induced cell invasion was primarily mediated by JNKs and p38 MAPK, whereas the involvement of ROS formation might be minimal. Our study suggests that overexpression of ErbB2 may augment ethanol-elicited signaling and promote ethanol-stimulated tumor metastasis.
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PMID:Overexpression of ErbB2 enhances ethanol-stimulated intracellular signaling and invasion of human mammary epithelial and breast cancer cells in vitro. 1291 29

Rapid engagement of the extracellular signal-regulated kinase (ERK) cascade via the Gq/11-coupled GnRH receptor (GnRHR) is mediated by transactivation of the epidermal growth factor receptor (EGFR). Here we show that the cross-talk between GnRHR and EGFR in gonadotropic cells is accomplished via gelatinases A and B (matrix metalloproteinases (MMPs) 2 and 9), identifying gelatinases as the first distinct members of the MMP family mediating EGFR transactivation by G protein-coupled receptors. Using a specific MMP2 and MMP9 inhibitor, Ro28-2653, GnRH-dependent EGFR transactivation was abrogated. Proving the specificity of the effect, transient transfection of alphaT3-1 cells with ribozymes directed against MMP2 or MMP9 specifically blocked EGFR tyrosine phosphorylation in response to GnRH stimulation. GnRH challenge of alphaT3-1 cells furthered the release of active MMP2 and MMP9 and increased their gelatinolytic activities within 5 min. Rapid release of activated MMP2 or MMP9 was inhibited by ribozyme-targeted down-regulation of MT1-MMP or MMP2, respectively. We found that GnRH-induced Src, Ras, and ERK activation were also gelatinase-dependent. Thus, gelatinase-induced EGFR transactivation was required to engage the extracellular-signal regulated kinase cascade. Activation of c-Jun N-terminal kinase and p38 MAPK by GnRH was unaffected by EGFR or gelatinase inhibition that, however, suppressed GnRH induction of c-Jun and c-Fos. Our findings suggest a novel role for gelatinases in the endocrine regulation of pituitary gonadotropes.
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PMID:Matrix metalloproteinases 2 and 9 mediate epidermal growth factor receptor transactivation by gonadotropin-releasing hormone. 1296 32

EBV latent infection is associated with the development of lymphoid and epithelial malignancies such as nasopharyngeal carcinoma (NPC). The EBV latent membrane protein 1 (LMP1) acts as a constitutively active tumor necrosis factor receptor and activates cellular signaling pathways such as c-Jun-NH(2)-terminal kinase, cdc42, Akt, and nuclear factor (NF)-kappaB. In epithelial cells, two regions of LMP1 induce specific forms of NF-kappaB. COOH-terminal activating region 2 only activates p52/p65 dimers, whereas COOH-terminal activating region 1 activates p50/p50, p50/p52, and p52/p65 dimers and also uniquely up-regulates the epidermal growth factor receptor (EGFR) at the mRNA level. Deregulation of specific NF-kappaB members is associated with the development of many cancers. In this study, the status of NF-kappaB activation was investigated in NPC to determine which NF-kappaB dimers may contribute to the development of NPC. Electrophoretic mobility shift assay, immunoblot, ELISA, and immunohistochemistry data demonstrate that in NPC, NF-kappaB p50 homodimers are specifically activated, and this activation is not dependent on LMP1 expression. Coimmunoprecipitation assays indicate that homodimers are bound to the transcriptional coactivator Bcl-3, and chromatin immunoprecipitation indicates that this complex is bound to NF-kappaB consensus motifs within the egfr promoter in NPC. The discrete yet striking NF-kappaB p50 activation in NPC suggests that p50/p50 homodimers may be important factors in the development of NPC and may contribute to oncogenesis through transcriptional up-regulation of target genes through their interaction with Bcl-3.
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PMID:Activation of nuclear factor-kappaB p50 homodimer/Bcl-3 complexes in nasopharyngeal carcinoma. 1467 88

The beta and gamma subunits of heterotrimeric GTP-binding proteins (Gbetagamma) were found to bi-directionally regulate the UV-induced activation of p38 and c-Jun NH(2)-terminal kinase, and the UV-induced activation of p38 was reported to enhance the resistance of normal keratinocytes to apoptosis. However, the signaling pathway downstream of Gbetagamma for this UV-induced p38 activation is not known. Thus, we examined the role of the Rho GTPase family in the regulation of UV-induced p38 activation by Gbetagamma. We found that overexpression of Gbetagamma increased the UV-induced activation of Cdc42 and that overexpression of constitutively active V12 Cdc42 increased the UV-induced p38 activation. Transfection of dominant negative N17 Cdc42 or small interfering RNA for Cdc42 blocked UV-induced p38 activation mediated by Gbetagamma in COS-1 and HaCaT cells. UV-induced p38 activation by Gbetagamma was blocked by overexpression of dominant negative p21-activated kinase (PAK)-interacting exchange factor beta (betaPix), and wild type betaPix stimulated the UV-induced p38 activation, which was blocked by N17 Cdc42. Gbetagamma increased the UV-induced activation of Ras, and the overexpression of V12 Ras increased UV-induced p38 activation, which was blocked by dominant negative betaPix. UV-induced p38 activation was inhibited by N17 Ras and a farnesyltransferase inhibitor, manumycin A. Gbetagamma also increased the UV-induced phosphorylation of the epidermal growth factor receptor (EGFR), and the UV-induced p38 activation was blocked by an EGFR kinase inhibitor, AG1478. From these results, we conclude that Gbetagamma mediates UV-induced activation of p38 in a Cdc42-dependent way and that EGFR, Ras, and betaPix act sequentially upstream of Cdc42 in COS-1 and HaCaT cells.
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PMID:Cdc42-dependent mediation of UV-induced p38 activation by G protein betagamma subunits. 1497 Feb 10

Ultraviolet A radiation from sunlight is a major human health concern, as it is not absorbed by the ozone layer and can deeply penetrate into the skin causing skin damage. To study the molecular mechanism involved in the ultraviolet A effect, human HaCaT keratinocytes were exposed to ultraviolet A at doses of 10 J per cm2 and 30 J per cm2. Ultraviolet A irradiation caused dose- and time-dependent apoptotic cell death, as evidenced by DNA fragmentation, flow cytometry, and the activation of caspase-3. To study the genes altered by ultraviolet A at an apoptosis-inducing dose (30 J per cm2), cells were harvested immediately after ultraviolet A treatment (0 h), and 6 h and 24 h after ultraviolet A exposure. Total RNA was extracted for microarray and real-time RT-PCR analysis, and cellular proteins were extracted for western blot analysis. Of the selected critical genes/proteins, the induction of c-Jun, c-myc, and p33ING1, and the repression of epidermal growth factor receptor, inhibitor of apoptosis protein, and survivin pathways, could be involved in ultraviolet-A-induced apoptosis. On the other hand, the late induction of cyclin D1 and cyclin-dependent kinase 4 was indicative of possible cell cycle recovery in surviving cells. Real-time RT-PCR analysis confirmed these results and a majority of the protein levels paralleled their corresponding RNA levels. In addition, ultraviolet A treatment altered the expression of genes involved in signal transduction, RNA processing, structural proteins, and metabolism in a time-dependent manner. This initial microarray analysis could advance our understanding of cellular responses to ultraviolet A exposure, and provide a platform from which to further study ultraviolet-A-induced apoptosis and carcinogenesis.
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PMID:Expression profiling of human keratinocyte response to ultraviolet A: implications in apoptosis. 1500 41

Tissue morphogenesis during development is regulated by growth factors and cytokines, and is characterized by constant remodeling of extracellular matrix in response to signaling molecules. MEK kinase 1 (MEKK1) is a mitogen-activated protein kinase (MAPK) kinase kinase originally identified as an upstream activator for several MAPK pathways. During mouse embryogenesis, MEKK1 controls cell shape changes and formation of actin stress fibers that are required for sealing epidermis in the embryos in a process known as eyelid closure. MEKK1-null mice display eye-open at birth (EOB), a phenotype found also in mice impaired in activin, a subgroup of the transforming growth factor beta (TGFbeta) family, or in epidermal growth factor receptor (EGFR) or its ligand TGFalpha, or in transcription factor c-Jun. Molecular analyses have revealed at least two signaling mechanisms in the control of eyelid closure. One is originated from the activins and is transduced through MEKK1, leading to transcription-independent actin stress fiber formation and transcription-dependent keratinocyte migration. Another is the TGFalpha/EGFR signal that is transduced through a MEKK1-independent pathway to the activation of the ERK MAPK, which also leads to keratinocyte migration. c-Jun might serve as a connection between the two pathways. As embryonic eyelid closure is a specific morphogenetic process that is easily detectable, genetic mutant mice with EOB will be ideal models to understand the signaling mechanisms in the control of epithelial cell migration and the morphogenetic process of epithelial sheet movement.
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PMID:The signaling pathways in tissue morphogenesis: a lesson from mice with eye-open at birth phenotype. 1531 93

A standard therapy used today for prostate cancer is androgen ablation by gonadotropin-releasing hormone analogs (GnRH-a). Although most patients respond to androgen ablation as an initial systemic therapy, nearly all cases will develop androgen resistance, the management of which is still a major challenge. Here, we report that GnRH-a can directly induce apoptosis of the androgen-independent prostate cancer-derived DU145 and PC3 cell lines. Using specific inhibitors, we found that the apoptotic effect of GnRH-a is mediated by c-Jun NH2-terminal kinase (JNK) and inhibited by the phosphatidylinositol 3'-kinase (PI3K)-protein kinase B (PKB) pathway. Indeed, in DU145 cells, GnRH-a activates the JNK cascade in a c-Src- and MLK3-dependent manner but does not involve protein kinase C and epidermal growth factor receptor. Concomitantly, GnRH-a reduces the activity of the PI3K-PKB pathway, which results in the dephosphorylation of PKB mainly in the nucleus. The reduction of PKB activity releases PKB-induced inhibition of MLK3 and thus further stimulates JNK activity and accelerates the apoptotic effect of GnRH-a. Interestingly, extracellular signal-regulated kinase is also activated by GnRH-a, and this occurs via a pathway that involves matrix metalloproteinases and epidermal growth factor receptor, but its activation does not affect JNK activation and the GnRH-a-induced apoptosis. Our results support a potential use of GnRH-a for the treatment of advanced prostate cancer and suggest that the outcome of this treatment can be amplified by using PI3K-PKB inhibitors.
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PMID:Gonadotropin-releasing hormone induces apoptosis of prostate cancer cells: role of c-Jun NH2-terminal kinase, protein kinase B, and extracellular signal-regulated kinase pathways. 1531 14

Exposure to cigarette smoke (CS) can lead to the development of lung cancer, but the molecular mechanisms underlying this process remain unclear. Given that activator protein 1 (AP-1) regulates genes involved in both physiologic and pathophysiologic processes, we have investigated the effects of CS on Jun and Fos family member expression and regulation using a nonmalignant human bronchial epithelial cell line, 1HAEo. Exposure to CS caused a marked upregulation of c-Jun, c-Fos, and Fra-1, but not of Fra-2, Jun-B, and Jun-D expression. Because Fra-1 is overexpressed in various tumors and upregulates genes associated with tumor progression, we further elucidated the mechanisms that control CS-stimulated fra-1 induction. CS stimulated fra-1 induction primarily at the transcriptional level. However, epidermal growth factor receptor (EGFR)-specific inhibitor, AG1478, completely suppressed CS-stimulated fra-1 expression. Similarly, the specific inhibitors of extracellular signal-regulated kinase (ERK), c-Jun NH2 terminal kinase (JNK), and p38 kinase signaling markedly suppressed fra-1 induction. Consistent with this finding, AG1478 blocked CS-stimulated ERK, JNK, and p38 phosphorylation. These results suggest that EGFR-activated multiple kinase signaling is essential for fra-1 induction. Furthermore, treatment of cells with GM6001, which inhibits matrix metalloproteinase activity, significantly suppressed CS-stimulated EGF shedding, EGFR and ERK kinase phosphorylation, and subsequent fra-1 induction. Collectively, our findings indicate an obligatory role for metalloproteinase-EGFR-mediated mitogen-activated protein kinase signaling in controlling CS-induced fra-1 expression.
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PMID:Matrix metalloproteinase/epidermal growth factor receptor/mitogen-activated protein kinase signaling regulate fra-1 induction by cigarette smoke in lung epithelial cells. 1552 91

Because beneficial effects of digitalis treatment in breast cancer patients have been suggested by epidemiological studies, we explored the mechanism of the growth inhibitory effects of these drugs on the estrogen receptor-negative human breast cancer cell line MDA-MB-435 s. Ouabain concentrations (100 nM or lower) that caused less than 25% inhibition of the pumping function of Na+/K+-ATPase had no effect on cell viability but inhibited proliferation. At the same concentrations, ouabain 1) activated Src kinase and stimulated the interaction of Src and Na+/K+-ATPase with epidermal growth factor receptor (EGFR); 2) caused a transient and then a sustained activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2); 3) increased the expression of p21Cip1 but decreased that of p53; and 4) activated c-Jun NH2-terminal kinase (JNK) but not p38 kinase. These data, in conjunction with our previous findings on the signaling role of Na+/K+-ATPase in other cells, suggest that ouabain-induced activation/transactivation of Src/EGFR by Na+/K+-ATPase leads to activation of ERK1/2, the resulting increase in the level of cell cycle inhibitor p21Cip1, and growth arrest. Cooperation of JNK with ERK1/2 in this process is also suggested. Digoxin and digitoxin concentrations close to or at the therapeutic plasma levels had effects on proliferation and ERK1/2 similar to those of ouabain, supporting the proposed potential value of digitalis drugs for the treatment of breast cancer.
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PMID:Digitalis-induced signaling by Na+/K+-ATPase in human breast cancer cells. 1560 3

Hyperosmolarity- and CD95 ligand (CD95L)-induced interactions between CD95 (Fas/APO-1) and the epidermal growth factor receptor (EGFR) involve EGFR-catalyzed CD95 tyrosine phosphorylation. Such interactions were studied by means of fluorescence resonance energy transfer (FRET) and CD95 receptor mutagenesis in Huh7 hepatoma cells. In cells cotransfected with EGFR-cyan fluorescent protein and CD95-yellow fluorescent protein, FRET studies showed a rapid, hyperosmolarity-induced, c-Jun-N-terminal kinase-dependent CD95-EGFR association in the cytosol with subsequent microtubule-dependent translocation of the protein complex to the plasma membrane. Inhibition of EGFR tyrosine kinase activity by AG1478 and cyclic adenosine monophosphate had no effect on hyperosmotic CD95-EGFR association in the cytosol but prevented CD95 tyrosine phosphorylation, targeting of the protein complex to the plasma membrane, and formation of the death-inducing signaling complex (DISC). The requirement of EGFR-mediated CD95 tyrosine phosphorylation for hyperosmotic and CD95L-induced CD95 membrane targeting and DISC formation was also shown in CD95 mutagenesis experiments. CD95 mutants with tyrosine-phenylalanine exchanges at positions 232 and 291 failed to translocate to the plasma membrane and to recruit Fas-associated death domain and caspase 8, although these mutants still associated with the EGFR in the cytosol in response to hyperosmolarity and CD95L. Cells transfected with these mutants were also resistant to CD95L-induced apoptosis. Single mutations of tyrosine 91, 232, and 291 failed to inhibit CD95 membrane targeting, DISC formation, or CD95L-induced apoptosis. In conclusion, we identify EGFR-CD95 interaction and phosphorylation of critical CD95 tyrosine residues as important early events in hyperosmotic and CD95L-induced CD95 activation and apoptosis induction.
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PMID:Fluorescence resonance energy transfer analysis of proapoptotic CD95-EGF receptor interactions in Huh7 cells. 1566 Mar 94

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