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

The mitogen activated protein (MAP) kinases or extracellular signal-regulated kinases (Erks) are activated in response to Ras expression or exposure to tumor promoters or to growth factors, and have been implicated in AP-1 transactivation in some models. We have shown that tumor promoter induced activation of the transcription factor AP-1 is required for induced neoplastic transformation in the Balb/C JB6 cell model. Jun and Fos family protein levels have been found not to be limiting for AP-1 response. The present study asks whether activation of Erks1 and 2 is required for AP-1 transactivation and transformation of JB6 cells and whether Erks might be targeted for cancer prevention. Expression of either of two different dominant negative kinase inactive Erk2 mutants in transformation sensitive (P+) JB6 cells substantially inhibited the tumor promoter induced activation of Erks1 and 2 and of AP-1 measured by a collagenase-luciferase reporter. Multiple mutant Erk2 expressing clonal lines were also rendered non-responsive to induced neoplastic transformation. These observations, together with our recent finding attributing AP-1 non-responsiveness to Erk deficiency in a clonal line of transformation resistant (P-) cells, argue for a requirement for Erks1 and/or 2 activation in AP-1 transactivation in the mouse JB6 neoplastic progression model, and suggest the utility of Erks as a prevention target.
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PMID:Expression of dominant negative Erk2 inhibits AP-1 transactivation and neoplastic transformation. 1003 Jun 73

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

The transcription factor AP-1 is activated in response to an incredible array of stimuli, including mitogenic growth factors, inflammatory cytokines, growth factors of the TGF-beta family, UV and ionizing irradiation, cellular stress, antigen binding, and neoplastic transformation. In this review, I discuss genetic evidence that supports a role for AP-1 in the cellular response to some of these stimuli and describe biochemical properties that might explain the ability of this transcription factor to activate different sets of genes in response to different stimuli.
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PMID:AP-1: one switch for many signals. 1057 22

Oncogenic (activated) Ras is a signal transducer that activates multiple effector-mediated signaling pathways leading to altered cell morphology, growth and differentiation, and neoplastic transformation. Activating mutations of Ras family genes have been detected in many types of human cancers, including lung cancer. However, the signaling mechanisms by which oncogenic Ras controls cancer cell growth is poorly characterized. This study evaluates the role of two specific signaling pathways, the c-Jun NH2-terminal kinase (JNK) pathway, and the extracellular signal-regulated kinase (ERK) pathway, in oncogenic Ras-induced morphological transformation of NCI-H82 human small cell lung cancer cells. In the NCI-H82 cell line, oncogenic Ras causes a marked and sustained activation of JNK but only has a modest effect on activation of the ERK pathway. The persistent JNK activation is associated with Ras-induced changes in cell morphology and enhanced transforming activity. Furthermore, JNK activation correlates with the induction of c-Jun expression, c-Jun phosphorylation on serines 63 and 73, and increased AP-1 activity. Deregulation of the JNK pathway using a dominant-negative mutant of JNK1, JNK1(APF), completely reverses the oncogenic Ras-induced transformed phenotype, including morphological reversion and inhibition of anchorage-independent growth and low-serum growth. Moreover, expression of JNK1(APF) leads to a decrease in c-Jun/AP-1 activity. In contrast, inhibition of ERK activation via a pharmacological approach using a mitogen-activated protein kinase/ERK kinase-specific inhibitor 2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one is unable to reverse the Ras-induced transformed morphology and c-Jun/AP-1 induction. These results demonstrate that the JNK/c-Jun/AP-1 pathway plays an essential role in mediating oncogenic Ras function in lung carcinoma cells.
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PMID:A dominant role for the c-Jun NH2-terminal kinase in oncogenic ras-induced morphologic transformation of human lung carcinoma cells. 1066 94

The serine/threonine kinase Cot is a member of the mitogen-activated protein kinase (MAPK) kinase kinase family implicated in cellular transformation. Enhanced expression of this protein has been shown to activate both the MAPK and the c-Jun N-terminal kinase (JNK) pathways and to stimulate the nuclear factor of activated T cells and NF-kappaB-dependent transcription. However, the nature of the normal functions of the Cot protein and the molecular mechanisms responsible for its oncogenic potential are still largely unknown. Here, we show that overexpression of the cot proto-oncogene is sufficient to stimulate the expression of c-jun and that, in turn, the activity of c-Jun is required for Cot-induced transformation. These observations prompted us to explore the molecular events by which Cot regulates c-jun expression. We found that Cot potently stimulates the activity of the c-jun promoter utilizing JNK-dependent and -independent pathways, the latter involving two novel members of the MAPK family, p38gamma (ERK6) and ERK5. Molecularly, this activity was found to be dependent on the ability of Cot to activate, in vivo, members of each class of the MAPK kinase superfamily, including MEK, SEK, MKK6, and MEK5. Furthermore, the use of dominant interfering molecules revealed that Cot requires JNK, p38s, and ERK5 to stimulate the c-jun promoter fully and to induce neoplastic transformation. These findings indicate that Cot represents the first example of a serine/threonine kinase acting simultaneously on all known MAPK cascades. Moreover, these observations strongly suggest that the transforming ability of Cot results from the coordinated activation of these pathways, which ultimately converge on the regulation of the expression and activity of the product of the c-jun proto-oncogene.
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PMID:Multiple mitogen-activated protein kinase signaling pathways connect the cot oncoprotein to the c-jun promoter and to cellular transformation. 1066 51

The JB6 cell culture model is used to identify molecular determinants of susceptibility to the promotion of neoplastic transformation. Clonal variants susceptible to transformation ('P+' cells) form numerous anchorage-independent colonies in soft agar upon treatment with the phorbol ester tumor promoter TPA, whereas resistant variants ('P-' cells) do not. We now report that there is significantly less binding of activator protein-1 (AP-1) to its DNA binding site in P- cells than in P+ cells. Gel supershift assays were performed to detect association of all seven AP-1 family members with their DNA binding site in TPA-treated and -untreated P+ and P- cells. Significantly lower DNA binding and protein expression of JunD were detected in P- cells than in P+ cells. c-Jun was detected in P+, but not P-, AP-1-DNA complexes, and c-Fos was detected in P-, but not P+, AP-1-DNA complexes. These and other phenotype-specific differences in abundance and composition of AP-1-DNA complexes may play a role in the resistance of P- cells to tumor promoter-induced transformation.
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PMID:Tumor promotion resistant cells are deficient in AP-1 DNA binding, JunD DNA binding and JunD expression and form different AP-1-DNA complexes than promotion sensitive cells. 1067 28

The products of the Jun family genes, c-Jun, JunB and JunD, are essential components of the activating protein-1 transcription factor complexes that are critically important in the control of cell growth, differentiation and neoplastic transformation. Although increased c-Jun expression has been reported in human colorectal tumors, expression of JunB and JunD in these tumors has not previously been characterized. In the current study, we examined 24 cases of human colorectal adenocarcinoma by western immunoblotting analysis and immunohistochemical staining for the expression of c-Jun, JunB and JunD proteins. Normal-appearing colonic mucosa distant from the tumors in the same colectomy specimens were used as a reference for comparison. The results showed that both c-Jun and JunB proteins were undetectable or barely detectable in normal mucosa but their expression levels were significantly increased in human colorectal adenocarcinomas. In contrast, JunD protein was present at high levels in normal mucosa and only showed a minimal increase in adenocarcinomas. These observations suggest that different Jun proteins may serve different roles in regulating colonic epithelial cell growth and in colorectal tumorigenesis.
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PMID:Expression of Jun family members in human colorectal adenocarcinoma. 1087 8

Activator protein-1 (AP-1), a dimeric complex consisting of proteins encoded by the jun and fos gene families, is a transcription factor induced by a variety of signals including those eliciting proliferation, differentiation, and neoplastic transformation. Although AP-1 has been widely studied in the last decade, physiological levels of AP-1 in different tissues are unclear. In the present study, we analyzed AP-1 activity in several organs (liver, kidney, brain, lung, spleen, heart, skin) of AP-1-luciferase transgenic mice of various ages. Results of these studies indicate that the level of AP-1 in young mice is much higher than that in older mice, and, second, that the skin contains considerably higher levels of AP-1 than other organs. The level of phosphorylated extracellular signal-regulated protein kinase (ERK) in skin was higher in 1- and 2-day-old mice than in mice of other ages. In addition, phosphorylated p38 kinase was high in 2-day-old and 1-wk-old mice, but phosphorylated c-Jun NH(2)-terminal kinase was not detected at any age. AP-1 activity and level of phosphorylated ERKs declined with maturation. These results imply that AP-1 activity mediated through an ERKs-dependent pathway may be involved in skin development.
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PMID:Organ-specific distribution of AP-1 in AP-1 luciferase transgenic mice during the maturation process. 1120 64

Many spices, including plants of the ginger family, possess anticarcinogenic activity. However, the molecular mechanisms by which they exert their antitumorigenic effects are unknown. Activator protein 1 (AP-1) has a critical role in tumor promotion, and blocking of tumor promoter-induced activation of AP-1 inhibits neoplastic transformation. Epidermal growth factor induces cell transformation and AP-1 activity. The purpose of this study was to investigate the effect of two structurally related compounds of the ginger family, [6]-gingerol and [6]-paradol, on EGF-induced cell transformation and AP-1 activation. Our results provide the first evidence that both block EGF-induced cell transformation but act by different mechanisms.
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PMID:Inhibition of epidermal growth factor-induced cell transformation and activator protein 1 activation by [6]-gingerol. 1122 68

A plethora of physiological and pathological stimuli induce and activate a group of DNA binding proteins that form AP-1 dimers. These proteins include the Jun, Fos and ATF subgroups of transcription factors. Recent studies using cells and mice deficient in individual AP-1 proteins have begun to shed light on their physiological functions in the control of cell proliferation, neoplastic transformation and apoptosis. Above all such studies have identified some of the target genes that mediate the effects of AP-1 proteins on cell proliferation and death. There is evidence that AP-1 proteins, mostly those that belong to the Jun group, control cell life and death through their ability to regulate the expression and function of cell cycle regulators such as Cyclin D1, p53, p21(cip1/waf1), p19(ARF) and p16. Amongst the Jun proteins, c-Jun is unique in its ability to positively regulate cell proliferation through the repression of tumor suppressor gene expression and function, and induction of cyclin D1 transcription. These actions are antagonized by JunB, which upregulates tumor suppressor genes and represses cyclin D1. An especially important target for AP-1 effects on cell life and death is the tumor suppressor p53, whose expression as well as transcriptional activity, are modulated by AP-1 proteins.
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PMID:AP-1 in cell proliferation and survival. 1140 35


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