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)

In conclusion, a multigene family (ERK) encoding protein kinases that have the capacity to convert tyrosine kinase signals to serine/threonine phosphorylation signals has been identified in animal and yeast cells. Protein kinases from this family have been shown to be phosphorylated on tyrosine and threonine in response to mitogens, as well as to have the capacity to autophosphorylate on these amino acid residues. In contrast, they apparently phosphorylate exogenous substrates on serine and/or threonine. Studies with cultured cells, Xenopus, and sea star oocytes have furthered our understanding of possible functions of Erks in vivo. These enzymes respond immediately to extracellular signals and are involved in G0-G1 transition (cultured cells), as well as in the M phase of oocyte maturation (Xenopus and sea star oocytes). Their usage of MAPs as substrates in vivo suggests a possible role of Erks in microtubule reorganization. ERK-encoded protein kinases use c-Jun, EGF receptor, and Raf-1 as potential substrates and can also reactivate dephosphorylated S6 kinase in vitro. Taken together, these data suggest that these enzymes play an important role in relaying the mitogenic signal by phosphorylating down-stream kinases and specific transcriptional factors, as well as having possible feedback function in the process of signal transduction. The results from the study of the yeast enzymes are pertinent to Erk activation in cells with nonmitogenic responses described above. In such cases, Erk protein kinases may act directly or indirectly on cyclins to arrest division and permit differentiation. The pathways influenced by ERK-like gene products in animal and yeast cells suggest that, depending on the downstream targets of substrates, transcriptional changes in a particular cell may occur to drive the cell cycle or, alternatively, withdrawal from the cell cycle may lead to specific differentiation events.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Erks: their fifteen minutes has arrived. 150 18

Irradiation of HeLa cells with short-wavelength ultraviolet light (UVC) induces the modification and activation of the preexisting transcription factors c-Fos-c-Jun (AP-1) and TCF/Elk-1, as well as the protein synthesis independent transcriptional activation of the c-fos and c-jun genes. This response to UVC is mediated via obligatory cytoplasmic signal transduction, involving Ras and Raf, Src, and MAP kinases. The UVC response is inhibited by prior down-modulation of growth factor receptor signaling upon growth factor prestimulation, by suramin (an inhibitor of receptor activation) or by expression of a dominant negative epidermal growth factor (EGF) receptor mutant. These data suggest the involvement of several growth factor receptors in the UVC response. Indeed, UVC induces the suramin-inhibitable immediate tyrosine phosphorylation of the EGF receptor.
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PMID:Involvement of growth factor receptors in the mammalian UVC response. 792 65

Overexpression of the erbB-2 gene contributes to aggressive behavior of various human adenocarcinomas, including breast cancer, through an unknown molecular mechanism. The erbB-2-encoded protein is a member of the ErbB family of growth factor receptors, but no direct ligand of ErbB-2 has been reported. We show that in various cells ErbB-2 can form heterodimers with both EGF receptor (ErbB-1) and NDF receptors (ErbB-3 and ErbB-4), suggesting that it may affect the action of heterologous ligands without the involvement of a direct ErbB-2 ligand. This possibility was addressed in breast cancer cells through either overexpression of ErbB-2 or by blocking its delivery to the cell surface by means of an endoplasmic reticulum-trapped antibody. We report that ErbB-2 overexpression enhanced binding affinities to both EGF and NDF, through deceleration of ligand dissociation rates. Likewise, removal of ErbB-2 from the cell surface almost completely abolished ligand binding by accelerating dissociation of both growth factors. The kinetic effects resulted in enhancement and prolongation of the stimulation of two major cytoplasmic signaling pathways, namely: MAP kinase (ERK) and c-Jun kinase (SAPK), by either ligand. Our results imply that ErbB-2 is a pan-ErbB subunit of the high affinity heterodimeric receptors for NDF and EGF. Therefore, the oncogenic action of ErbB-2 in human cancers may be due to its ability to potentiate in trans growth factor signaling.
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PMID:ErbB-2 is a common auxiliary subunit of NDF and EGF receptors: implications for breast cancer. 861 1

We previously reported that introduction of H-ras oncogene decreases the epidermal growth factor (EGF) binding activity to cell surface EGF receptor in mouse Balb/3T3. In this study, we have further isolated four H-ras transfectants, four v-myc transfectants and three both H-ras and v-myc (H-ras/v-myc) transfectants of mouse Balb/3T3 cells. In comparison with introduction of v-myc alone or both H-ras and v-myc oncogene, introduction of H-ras alone resulted in a loss of [125I]EGF binding activity to the cell surface EGF receptor. RT-PCR analysis also showed much lower levels of EGF receptor gene expression in H-ras transfectants compared to that of parental untransformed cells (Balb-Neo1), v-myc and H-ras/v-myc transfectants. Our results demonstrated the activated binding of a transcription factor, Stat1 p84/p91, which directly interacts with EGF receptor, to c-sis-inducible element (SIE) in both v-myc and H-rs/v-myc transfectants, but not in H-ras transfectants. Among transcription factors which we have analysed, activator protein 1 (AP-1) but not SP-1 was modulated by H-ras. Gel shift assays demonstrated the mobility pattern of TPA-responsive element (TRE) binding complex with AP-1 derived from H-ras transfectants migrated faster than those from Balb-Neo1, v-myc and H-ras/v-myc. Expression of c-Jun and Fra-1 was increased more than threefold in H-ras transfectants compared with Balb-Neo1, v-myc and H-ras/v-myc transfectants, but that of c-Fos, Jun B and SP-1 was unchanged. Both transient and permanent expression of H-ras enhanced AP-1 activity in mouse cells, but further co-introduction of dominant negative c-jun mutant encoding a transcriptionally inactive product inhibited the H-ras dependent AP-1 induction. Transfection of the dominant negative c-jun mutant also restored down-regulation of EGF binding by activated H-ras oncogene. Down-regulation of EGf receptor by activated H-ras and the possible involvement of a transcription factor, AP-1 will be discussed.
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PMID:Regulation of epidermal growth factor receptor by activated H-ras and V-myc oncogenes in mouse Balb/3T3 cells: possible roles of AP-1. 862 82

Epidermal growth factor (EGF) receptor was shown to be involved in the activation pathway of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) cascade not only by EGF, but also by UV radiation or osmotic stress. This paper describes a specific interaction between the COOH-terminal SH3 domain of Grb2 and the NH2-terminal regulatory domain of MEKK1 in ER22 cells overexpressing the EGF receptor. This interaction results in the formation of a constitutive complex between Grb2 and MEKK1 in both proliferating and resting cells. EGF stimulation causes this complex to be rapidly and transiently recruited by Shc proteins. The subsequent release of the Grb2-MEKK1 complex from Shc proteins correlates with JNK activation. Transfection of the NH2-terminal regulatory domain of MEKK1 specifically inhibits EGF-dependent JNK activation indicating that Grb2 is involved in MEKK1 activation. Thus, adaptor proteins have a new role in the regulation of the SAPK/JNK cascade after EGF stimulation.
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PMID:Grb2 interaction with MEK-kinase 1 is involved in regulation of Jun-kinase activities in response to epidermal growth factor. 973 14

The tumor suppressor PTEN dephosphorylates focal adhesion kinase (FAK) and inhibits integrin-mediated cell spreading and cell migration. We demonstrate here that expression of PTEN selectively inhibits activation of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway. PTEN expression in glioblastoma cells lacking the protein resulted in inhibition of integrin-mediated MAP kinase activation. Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF)- induced MAPK activation were also blocked. To determine the specific point of inhibition in the Ras/Raf/ MEK/ERK pathway, we examined these components after stimulation by fibronectin or growth factors. Shc phosphorylation and Ras activity were inhibited by expression of PTEN, whereas EGF receptor autophosphorylation was unaffected. The ability of cells to spread at normal rates was partially rescued by coexpression of constitutively activated MEK1, a downstream component of the pathway. In addition, focal contact formation was enhanced as indicated by paxillin staining. The phosphatase domain of PTEN was essential for all of these functions, because PTEN with an inactive phosphatase domain did not suppress MAP kinase or Ras activity. In contrast to its effects on ERK, PTEN expression did not affect c-Jun NH2-terminal kinase (JNK) or PDGF-stimulated Akt. Our data suggest that a general function of PTEN is to down-regulate FAK and Shc phosphorylation, Ras activity, downstream MAP kinase activation, and associated focal contact formation and cell spreading.
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PMID:Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways. 983 64

We have reported that angiotensin II induces the epidermal growth factor (EGF) receptor transactivation leading to extracellular signal-regulated kinase (ERK) activation in rat vascular smooth muscle cells. Here, we report that the EGF receptor kinase inhibitor AG1478 and the ERK kinase inhibitor PD98059 markedly inhibited angiotensin II-induced c-Fos expression and protein synthesis but not c-Jun expression in these cells. These data suggest that the EGF receptor transactivation and subsequent ERK activation are indispensable for angiotensin II-mediated growth promotion of vascular smooth muscle cells providing a new mechanistic insight whereby angiotensin II contributes abnormal vascular remodeling.
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PMID:Epidermal growth factor receptor is indispensable for c-Fos expression and protein synthesis by angiotensin II. 1044 Jan 5

Multiple lines of evidence suggest that cyclooxygenase-2 (COX-2) is an important target for preventing epithelial malignancies. Little is known, however, about the expression of COX-2 in gynecological malignancies. By immunoblot analysis, COX-2 was detected in 12 of 13 cases of cervical cancer but was undetectable in normal cervical tissue. Immunohistochemistry revealed COX-2 in malignant epithelial cells. COX-2 was also expressed in cervical intraepithelial neoplasia. The mechanism by which COX-2 is up-regulated in cervical cancer is unknown. Because the epidermal growth factor (EGF) receptor is commonly overexpressed in cervical cancer, we investigated whether EGF could induce COX-2 in cultured human cervical carcinoma cells. Treatment with EGF markedly induced COX-2 protein, COX-2 mRNA, and stimulated COX-2 promoter activity. The induction of COX-2 by EGF was suppressed by inhibitors of tyrosine kinase activity, phosphatidylinositol 3-kinase, mitogen-activated protein kinase kinase, and p38 mitogen-activated protein kinase. Moreover, overexpressing dominant-negative forms of extracellular signal-regulated kinase 1, c-Jun NH2-terminal kinase, p38, and c-Jun blocked EGF-mediated induction of COX-2 promoter activity. Taken together, these findings suggest that deregulation of the EGF receptor signaling pathway may lead to enhanced COX-2 expression in cervical cancer.
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PMID:Cyclooxygenase-2 is overexpressed in human cervical cancer. 1123

Lysophosphatidic acid (LPA) is a bioactive lipid mediator and important component of serum. Studies over the past several years which have documented diverse effects of LPA on multiple types of airway cells and which suggest possible involvement of LPA in lung disease are reviewed here. LPA enhances contractility of airway smooth muscle. It also stimulates proliferation of cultured airway smooth muscle cells and exhibits a striking synergism with epidermal growth factor (EGF) for stimulating mitogenesis. Recent studies of the molecular components and signaling pathways mediating synergism are described, including LPA-induced upregulation of EGF receptors and activation of multiple transcription factors by both LPA and EGF. A model for the effects of LPA and EGF on mitogenesis that includes EGF receptor upregulation and synergism between Ras and Rho for activation of the transcription factor AP-1 is presented. LPA stimulates fibronectin secretion and filopodia extension in airway epithelial cells as well as proliferation and collagen gel contraction by lung fibroblasts. A hypothesis for LPA involvement in the airway repair and remodeling, which contribute to the pathology of asthma and other airway diseases, is presented, and future directions for research into the roles of LPA in airway function and disease are suggested.
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PMID:Lysophosphatidic acid in airway function and disease. 1206 34

Clusterin is a ubiquitous secretory glycoprotein that is known to suppress certain forms of apoptosis. Since apoptosis and proliferation are two opposing cellular events, it remains unclear if clusterin has any effect on cellular proliferation. The objective of the present study was to examine the effects of clusterin on proliferation in a prostate cancer cell line, LNCaP. We found that clusterin inhibited EGF-mediated proliferation in these cells, as measured by (3)H-thymidine incorporation and by cell counting. Clusterin did not bind with EGF nor did it block phosphorylation of the EGF receptor. Treatment of LNCaP cells with EGF resulted in a transient increase in the expression of both c-Fos and c-Jun. Addition of clusterin to these cultures significantly down-regulated the protein level of c-Fos, but not c-Jun. These results demonstrated a novel biological role for clusterin. Clusterin is not only anti-apoptotic but also anti-proliferative. The anti-proliferative event maybe associated with a down-regulation of c-Fos.
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PMID:A novel anti-proliferative property of clusterin in prostate cancer cells. 1240 41


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