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)

We have recently reported that neoplastic transformation of two rat thyroid epithelial cell lines by retroviruses carrying the v-mos and v-ras Ki oncogenes is associated with a drastic increase of AP-1 activity. The most important effects were represented by the dramatic junB and fra-1 gene induction, which was abolished by the block of the transformation-induced HMGI-C protein synthesis. Here, we have further characterized the transformation-dependent AP-1 activity, by analysing the expression of different jun- and fos-related components, in rat thyroid cell lines transformed by several oncogenes, in human thyroid carcinoma cell lines, and in naturally occurring human thyroid tumours. A significant increase of Fra-1 and JunB protein levels was detected in all oncogene transformed rat thyroid cell lines. Fra-1 gene induction was demonstrated to occur also in human thyroid carcinoma cell lines and tissues. Conversely, c-Jun and JunD proteins, rather than JunB, accumulated in human thyroid carcinoma cell lines. An induction of AP-1 target genes was also detected both in rat and human thyroid transformed cell lines. Therefore, in vivo and in vitro thyroid cell transformation is associated with important compositional changes in the AP-1 complex and an increased transcriptional activity.
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PMID:Increase in AP-1 activity is a general event in thyroid cell transformation in vitro and in vivo. 969 May 19

Ras activates a multitude of downstream activities with roles in cellular proliferation, invasion and metastasis, differentiation, and programmed cell death. In this work we have evaluated the requirement of extracellular signal-regulated protein kinase (ERK), c-Jun NH2-terminal kinase kinase (JNKK), and c-Jun/AP-1 activities in transformation and extracellular matrix invasion of ras oncogene expressing NIH 3T3 fibroblasts by expressing stable mutant genes that constitutively inhibit these activities. Whereas the inhibition of ERK activity reverts the transformed and invasive phenotype, the inhibition of the JNK pathway and AP-1 trans-activating activities by JNKK[K129R] and c-Jun(TAM67) had no effect on the ability of the ras oncogene-expressing cells to grow in soft agar or invade Matrigel basement membrane. Thus an elevated JNK activity and/or c-Jun/AP-1 trans-activating activity are not absolute requirements for ras transformation or invasion through basement membrane, and the dependence on AP-1 activity for transformation is cell-specific. However, inhibition of JNK kinase (JNKK) in ras-transformed cells with normally elevated JNK activity switches the protease-dependent invasive phenotype from a urokinase plasminogen activator (uPA)-dependent to a cathepsin L (CL)-dependent invasive phenotype. Conversely, treatment of ras-transformed cells of low constitutive JNK activity with the JNK stimulator, anisomycin, converts the protease mRNA levels from those characteristic of a CL-dependent to a uPA-dependent phenotype. These protease phenotypes can be duplicated in untransformed NIH 3T3 cells that express platelet-derived growth factor receptors and m1 muscarinic receptors that selectively stimulate the ERK or JNK pathways, respectively. It is concluded that high ERK activity is required for both protease phenotypes, whereas the JNK pathway and c-Jun/AP-1 activity are not required for transformation but regulate a switch between uPA and CL protease phenotypes in both transformed and untransformed cells. In ras-transformed NIH 3T3 fibroblasts, the uPA- and CL-dependent protease phenotypes are redundant in their ability to invade through basement membrane.
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PMID:Role of mitogen-activated protein kinases and c-Jun/AP-1 trans-activating activity in the regulation of protease mRNAs and the malignant phenotype in NIH 3T3 fibroblasts. 987 19

Downregulation of the colon tumour-suppressor homeobox gene Cdx-2 by oncogenic ras Constitutive activation of the ras proto-oncogene is a frequent and early event in colon cancers, but the downstream nuclear targets are not fully understood. The Cdx-1 and Cdx-2 homeobox genes play crucial roles in intestinal cell proliferation and differentiation. In addition, Cdx-2 is a colonic tumour-suppressor gene, whereas Cdx-1 has oncogenic potential. Here, we show that constitutive activation of ras alters Cdx-1 and Cdx-2 expression in human colonic Caco-2 and HT-29 cells that harbour a normal ras proto-oncogene. Oncogenic ras downregulates Cdx-2 through activation of the PKC pathway and a decline in activity of the Cdx-2 promoter AP-1 site. This decline results from a PKC-dependent decrease in the relative expression of c-Jun, an activator of Cdx-2 transcription, compared to c-Fos, an inhibitor of Cdx-2. Unlike Cdx-2, Cdx-1 is upregulated by oncogenic ras and this effect is mediated by activation of the MEK1 pathway. These results indicate that oncogenic ras activation has opposite effects on Cdx-1 and Cdx-2 expression through distinct signalling pathways and they provide the first evidence for a functional link between ras activation and the downregulation of the Cdx-2 tumour-suppressor gene in colon cancer cells.
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PMID:Downregulation of the colon tumour-suppressor homeobox gene Cdx-2 by oncogenic ras. 992 23

CCK stimulates pleiotrophic responses in pancreatic acinar cells; however, the intracellular signaling pathways involved are not well understood. To evaluate the role of the ras gene product in CCK actions, a strategy involving in vitro adenoviral-mediated gene delivery of a dominant-negative mutant Ras (RasN17) was utilized. Isolated acini were infected with various titers of either a control adenovirus or an adenoviral construct expressing RasN17 for 24 h before being treated with CCK. Titer-dependent expression of RasN17 in the acini was confirmed by Western blotting. Infection with control adenovirus [10(6)-10(9) plaque-forming units/mg acinar protein (multiplicity of infection of approximately 1-1,000)] had no effect on CCK stimulation of acinar cell amylase release, extracellular-regulated kinase (ERK) or c-Jun kinase (JNK) kinases, or DNA synthesis. In contrast, infection with adenovirus bearing rasN17 increased basal amylase release, inhibited CCK-mediated JNK activation, had no effect on CCK activation of ERK, and inhibited DNA synthesis. These data demonstrate important roles for Ras in specific actions of CCK on pancreatic acinar function.
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PMID:Adenovirus-mediated gene transfer of RasN17 inhibits specific CCK actions on pancreatic acinar cells. 995 Aug 25

The nuclear factor AP-1, a large family of transcription factors composed of the Jun and Fos protein families, plays a role in the differentiation of various cells; the role of the AP-1 factors in intestinal differentiation is not known. Members of the AP-1 family can be activated by the Ras pathway and, in addition, Ras appears to be important for gut differentiation. The purpose of this study was to determine whether AP-1 activity is altered in the Caco-2 cell line, which spontaneously differentiates to a small bowel phenotype after confluency, and the Caco-2-ras cell line, which exhibits differentiated properties regardless of culture conditions. AP-1 binding activity, consisting of c-Jun, JunD, c-Fos and Fra-2 proteins, was increased in Caco-2 cells at 3 days postconfluency, a time point associated with G1 block and cessation of proliferation. Steady state levels of JunD were increased at day 3 postconfluency as determined by Western blot. Furthermore, AP-1 binding was increased in preconfluent Caco-2-ras cells compared with parental Caco-2 cells, suggesting that AP-1 induction may be mediated by the Ras pathway. The early induction of AP-1 binding activity suggests a role for these proteins in the differentiation of the Caco-2 intestinal cell line.
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PMID:Enterocyte-like differentiation of the Caco-2 intestinal cell line is associated with increases in AP-1 protein binding. 1002 48

The comparative tumorigenicity in rats and nude mice of cell lines derived from FR3T3 and transformed by either c-jun, ras, SV40 lt, or bovine papilloma virus type 1 (BPV1) oncogenes was investigated. c-Jun-transformed cells were as tumorigenic and metastatic as Ras-transformed cells. Latencies were short, and numerous pulmonary metastases were observed in all injected animals. In contrast, tumors induced by s.c. injection of SV40-transformed cells developed slower, and none of the animals who received injections i.v. presented with metastases. BPV1-transformed cells had an intermediate tumorigenic and metastatic activity. Microvessels present in the different tumors were revealed by immunostaining with Griffonia (Bandeiraea) Simplicifolia lectin 1. Tumors obtained with c-Jun-transformed cells exhibited more neovascularization than those induced by the other oncogenes. By comparison to FR3T3 cells or SV40- or BPV1-transformed cells, c-Jun-transformed fibroblasts repress the antiangiogenic thrombospondin-1 and SPARC genes, whereas we found that they express higher levels of gene expression of the angiogenic vascular endothelial growth factor. Finally, as compared with cells before passage in animals, thrombospondin-1, SPARC, and VEGF gene expression was also deregulated in cell lines isolated from primary tumors induced by BPV1-transformants. Our results indicate that the high transforming potential of c-Jun, evidenced as soon as transformation is established in vitro, correlates with deregulation of gene expression of both angiogenic and antiangiogenic factors leading to rapid neovascularization of tumors.
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PMID:Rat embryo fibroblasts transformed by c-Jun display highly metastatic and angiogenic activities in vivo and deregulate gene expression of both angiogenic and antiangiogenic factors. 1009 33

The T1 gene encodes a protein, which shares homology with the IL-1 receptors. In fibroblasts, T1 is induced by growth factors and in response to the onset of oncogene expression. The c-fos gene is transiently activated in these situations and was shown to be the major mediator of T1 gene induction. In contrast, the sustained expression of a ras oncogene in NIH3T3 cells resulted in the downregulation of basal T1 gene activity and the attenuation of T1 gene induction in response to mitogenic signals. Likewise, the immediate early genes encoding c-Fos, FosB, and Fra-2 are repressed in these cells. T1 gene repression could be overcome by the forced expression of c-fos in ras transformed fibroblasts. Thus, the lack of c-fos gene expression is the likely cause for ras mediated T1 gene repression. Fra-1, in contrast to the other three members of the Fos family, is permanently synthesized in high amounts in ras transformed NIH3T3 fibroblasts. We show that AP-1, which is abundant in these cells throughout the whole cell cycle, consists predominantly of Fra-1/c-Jun and Fra1/JunD heterodimers. We provide evidence that Fra1/c-Jun heterodimers are responsible for the repression of c-fos gene induction following serum stimulation. The introduction of a dominant negative version of c-Jun into ras transformed fibroblasts was able to rescue c-fos gene induction in response to serum stimulation, further demonstrating that AP-1 is indeed involved in c-fos gene repression. We conclude that oncogenic ras mediates the activation of the fra-1 gene which results in elevated AP-1 activity throughout the cell cycle. Fra-1 containing AP-1 complexes repress the c-fos and possibly other immediate early genes thereby preventing the induction of certain delayed early genes such as the T1 gene in response to mitogenic stimulation.
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PMID:Attenuated expression of the serum responsive T1 gene in ras transformed fibroblasts due to the inhibition of c-fos gene activity. 1020 34

Although the frequency of activated Ki-ras genes is high in human colorectal tumors, much less is known of activated Ki-ras-mediated signaling pathways. Using gene targeting, we examined HCT116 cells that contain the Gly-13-->Asp mutation of Ki-ras and activated Ki-ras-disrupted clones derived from HCT116. 12-O-Tetradecanoylphorbol-13-acetate (TPA) induced immediate early genes, such as c-Jun, c-Fos, and Egr-1 in activated Ki-ras-disrupted clones, whereas c-Jun induction was rare in HCT116. TPA induced both phosphorylation of stress-activated protein kinase kinase 1 (SEK1) and c-Jun NH2-terminal kinase (JNK) in the activated Ki-ras-disrupted clones but not in HCT116. On the other hand, TPA-induced mitogen-activated protein kinase kinase 1/2 (MEK1/2)-extracellular signal-regulated kinase (ERK) activation was equally induced between HCT116 and the Ki-ras-disrupted clones. Furthermore, TPA-induced SEK1-JNK activation was observed in a DLD-1-derived activated Ki-ras-disrupted clone but not in DLD-1. The TPA-induced SEK1-JNK activation in these disrupted clones was completely inhibited by the protein kinase C (PKC) inhibitor, GF109203X (1 microM), but not by another PKC inhibitor, H7 (50 microM), whereas TPA-induced MEK1/2-ERK activation was partially and completely inhibited by GF109203X (1 microM) and H7 (50 microM), respectively. A phosphoinositol 3-kinase inhibitor, LY294002, did not inhibit the TPA-induced SEK1-JNK activation. Taken together, these results suggest that activated Ki-Ras-mediated signals are involved in the SEK1-JNK pathway through a PKC isotype that is distinct from that involved in MEK1/2-ERK activation in human colon cancer cells and independent of phosphoinositol 3-kinase activation, and the imbalance between ERK and JNK activity caused by activated Ki-Ras may play critical roles in human colorectal tumorigenesis.
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PMID:Activated Ki-Ras suppresses 12-O-tetradecanoylphorbol-13-acetate-induced activation of the c-Jun NH2-terminal kinase pathway in human colon cancer cells. 1034 56

The protein kinase C (PKC) family, which functions through serine/threonine kinase activity, is involved in signal transduction pathways necessary for cell proliferation and differentiation. Its critical role in processes relevant to neoplastic transformation and tumor invasion renders PKC a potentially suitable target for anticancer therapy. To explore whether antisense blocking of PKCalpha would inhibit the neoplastic properties in tumor cells, human lung carcinoma LTEPa-2 cells were transfected with a recombinant plasmid, pXJ41-CKPalpha, with PKCalpha cDNA inserted in the antisense orientation. In LT.AS4 cell clones stably expressing antisense PKCalpha mRNA, the amounts of PKCalpha protein and total PKC activity were decreased when compared to control cells. The expression of antisense PKCalpha markedly inhibited the cell proliferation rate, colony forming efficiency in soft agar, and tumorigenecity in nude mice. Furthermore, the mRNA levels of oncogenes (Ha-ras, c-jun, and c-fos) were seen to decrease to varying degrees. Reduced DNA binding activity of transcription factor AP-1 was also observed using gel shift analysis, suggesting that one major molecular mechanism by which PKCalpha can exert its effects on cell growth and transformation is through regulation of AP-1 transcription factor activity. Taken together, these data provide evidence for the ability of antisense PKCalpha expression to reverse the transformed phenotype of human lung carcinoma cells and support the development of PKCalpha inhibitors for the clinical treatment of cancers.
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PMID:Antisense inhibition of protein kinase Calpha reverses the transformed phenotype in human lung carcinoma cells. 1038 39

Epidermal growth factor (EGF) enhances the expression of the keratinocyte terminal differentiation marker SPRR2A, when added to monolayers of basal keratinocytes, induced to stratify by increasing the extracellular calcium concentration. A similar stimulation is found during suspension-induced differentiation in methylcellulose. This effect, which is observed after several hours of EGF addition, is restricted to terminally differentiating keratinocytes and is dependent on PKC signaling. EGF also transiently activates the Ras signaling pathway, with a maximum induction after 10 min (Medema et al., 1994, Mol. Cell. Biol. 14, 7078-7085). The cellular effects of activated Ras were determined by transient transfection of Ha-ras(Leu-61) into normal human keratinocytes. Activated Ras completely inhibited PKC-mediated expression of SPRR2A. This inhibition is mediated via c-Jun as it is reversed by a dominant-negative c-Jun mutant (cJunDelta6/194) and c-Jun can substitute for activated Ras. The inhibitory effect is targeted to a 150-bp minimal promoter region, which is essential and sufficient for SPRR2A expression during keratinocyte terminal differentiation. This indicates that the Ras and PKC pathways, which both can be triggered by EGF, although at different time points, have opposite effects on SPRR2A gene expression.
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PMID:Opposite effects of Ras or PKC activation on the expression of the SPRR2A keratinocyte terminal differentiation marker. 1041 1


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