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)

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

Human breast tumors that are initially responsive to tamoxifen (TAM) eventually relapse during treatment. Estrogen receptor (ER) expression and function are often preserved in these tumors, and clinical evidence suggests that this relapse may be related to TAM's known agonistic properties. ER can interact with the activator protein-1 (AP-1) transcription factor complex through protein-protein interactions that are independent of ER DNA binding and, in certain ER-positive cells, this may allow TAM to exert an agonist response on AP-1-regulated genes. We, therefore, assessed both AP-1 DNA binding and the known AP-1 activating enzyme, c-Jun NH2-terminal kinase (JNK), in a panel of 30 ER-positive primary human breast tumors with acquired TAM resistance, as compared to a matched panel of 27 untreated control ER-positive breast tumors and a separate control set of 14 primary tumors, which included 7 ER-positive tumors that were growth-arrested by 3 months of preoperative TAM. AP-1 DNA binding activity was measured from cryopreserved tumor extracts using a labeled oligonucleotide probe containing a consensus AP-1 response element by electrophoretic mobility shift assay. JNK was first extracted from the tumor lysates by incubation over a Sepharose-bound c-Jun(1-89) fusion protein, and its activity was then measured by chemiluminescent Western blot by detection of the phosphorylated product using a phospho-Jun(Ser-63)-specific primary antibody. The set of control ER-positive breast tumors growth arrested by TAM showed no significant difference from untreated control tumors in their AP-1 DNA binding and JNK activities. In contrast, there was a significant (P < 0.001) increase in mean AP-1 DNA binding activity for the panel of ER-positive TAM-resistant (TAM-R) tumors as compared to its matched control panel of untreated tumors. Mean JNK activity in the TAM-R tumors was also significantly higher than that found in the untreated tumors (P = 0.038). Overall, there was no significant correlation between JNK activity and AP-1 DNA binding; however, regression analysis showed that, for any given level of JNK activity, the TAM-R tumors possessed a 3.5-fold increase in AP-1 DNA binding activity as compared to the untreated tumors. These findings indicate that, when compared to untreated ER-positive primary breast tumors, TAM-R tumors demonstrate significantly increased levels of AP-1 DNA binding and JNK activity, consistent with experimental models suggesting that TAM-stimulated ER-positive tumor growth may be mediated by enhanced AP-1 transcriptional activity. These observations support the need for further evaluation of these markers in breast tumors as predictors of TAM resistance.
Clin Cancer Res 1999 Feb
PMID:Increased activator protein-1 DNA binding and c-Jun NH2-terminal kinase activity in human breast tumors with acquired tamoxifen resistance. 1003 72

Dietary energy restriction (DER) inhibits carcinogenesis in numerous animal models. DER is a potent and reproducible inhibitor of two-stage mouse skin carcinogenesis when administered during the promotion phase. Previous research demonstrated that adrenalectomy abolished cancer prevention by food restriction. Several lines of evidence suggest that glucocorticoid elevation in the DER mouse mediates the prevention of skin cancer. Our research tested the hypothesis that elevated glucocorticoid hormone activates the glucocorticoid receptor (GR) and that this activated receptor interferes with the activator protein-1 (AP-1) transcription factor. Induction of AP-1 by the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) is essential to tumor promotion. We have been unable to demonstrate elevated activated GR in the epidermis of the DER mouse, perhaps because only indirect strategies have been possible with the use of epidermis from DER mice. However, DER blocked the induction of AP-1 and c-jun, a constituent protein of AP-1, in the epidermis of mice. Current studies are focused on the inhibition of signaling down the MAP-1/Raf-1 kinase pathway that leads to induction of constituent proteins of AP-1, including c-Jun. Although several pathways lead to the induction of AP-1 transcriptional activity, the MAP-1/Raf-1 pathway can be activated by protein kinase C (PKC); previous studies from our laboratory demonstrated an inhibition of PKC activity and a reduction in selected isoforms of PKC in the epidermis of the DER mouse. Our current working hypothesis is that elevated glucocorticoid hormone in the DER mouse reduces the amount and activity of PKC isoforms important in the activation of MAP-1/Raf-1 kinase pathway. We propose that this results in attenuation in the induction of the AP-1 transcription factor by TPA. Because AP-1 induction by TPA is obligatory for mouse skin promotion, we propose this as an essential component of the mechanism of DER prevention of mouse skin carcinogenesis.
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PMID:Glucocorticoid mediation of dietary energy restriction inhibition of mouse skin carcinogenesis. 1006 35

Chronic and excessive ethanol consumption is associated with cellular proliferation, fibrosis, cirrhosis, and cancer of the liver. The critical event in early alcohol-induced hepatic injury is an alcohol-induced activation (cell proliferation and increased fibrogenesis) of hepatic stellate cells. However, the mechanisms by which alcohol causes proliferative activation in hepatic stellate cells have not been identified. An important characteristic of alcohol-induced injury is impaired vitamin A nutritional status. The demonstration that retinoic acid is the most physiologically active derivative of vitamin A and the discovery of retinoic acid receptors provide a mechanistic basis for understanding the actions of vitamin A and alcohol on hepatic cell proliferation. Recent studies have demonstrated that chronic alcohol intake can reduce hepatic retinoic acid concentrations, diminish retinoid signaling, and enhance activator protein-1 (AP-1 (c-Jun and c-Fos)) expression in rat liver. These are the possible biochemical and molecular mechanisms whereby ethanol ingestion results in hepatic stellate cell proliferative activation and hepatic fibrogenesis.
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PMID:Chronic alcohol intake interferes with retinoid metabolism and signaling. 1007 3

Benzyl isothiocyanate (BIT), a microconstituent found in cruciferous vegetables, is known to be a potent inducer of the detoxification enzyme, NAD(P)H: quinone reductase (QR). QR catalyzes a two-electron transfer to a wide variety of redox-cycling species, including quinones, transforming them into dihydrodiols, thereby preventing the mutation of DNA and reducing cancer risk. The upstream signaling mechanisms that lead to the induction of QR remain unclear. The 5' promoter region of the human QR gene contains the cis-acting AP-1 and NFkappaB transcription factor binding sites. When HT29 human colon cells were exposed to 25microM benzyl isothiocyanate, AP-1 binding increased, beginning at 3 hours and increasing until 16 hours. NFkappaB binding also increased, reaching a maximum at around 6 hours. We also found that c-Jun N-terminal kinase (JNK), which phosphorylates c-Jun, a component of AP-1, was activated 9-fold over controls, beginning at 60 minutes. The temporal sequence of these events supports the idea that JNK is involved in the induction of QR and that this is an initial event preceding an increase in transcription factor binding and subsequent QR activity.
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PMID:Temporal effects of the detoxification enzyme inducer, benzyl isothiocyanate: activation of c-Jun N-terminal kinase prior to the transcription factors AP-1 and NFkappaB. 1009 25

Loss of DNA mismatch repair has been observed in a variety of human cancers. Recent studies have shown that loss of DNA mismatch repair results in resistance to cisplatin but not oxaliplatin, suggesting that the mismatch repair proteins serve as a detector for cisplatin but not oxaliplatin adducts. To identify the signal transduction pathways with which the detector communicates, we investigated the effect of loss of DNA mismatch repair on activation of known damage-responsive pathways, and recently reported that cisplatin differentially activates c-Jun NH2-terminal kinase (JNK) and c-Abl in repair-proficient vs.-deficient cells. In the current study, we directly compared differential activation of these pathways by cisplatin vs. oxaliplatin. The results confirm that cisplatin activates JNK kinase 5.7 +/- 1.5 (s.d.)-fold more efficiently in DNA mismatch repair-proficient than repair-deficient cells, and that the c-Abl response to cisplatin is completely absent in DNA mismatch repair-deficient cells. In contrast, there was no detectable activation of the JNK or c-Abl kinases in DNA mismatch repair-proficient or -deficient cells exposed to oxaliplatin. The present study demonstrates that, despite the similarity of the adducts produced by cisplatin and oxaliplatin, they appear to be recognized by different detectors. The DNA mismatch repair system plays an important part in the recognition of cisplatin adducts, and activation of both the JNK and c-Abl kinases in response to cisplatin damage is dependent on the detector function of the DNA mismatch repair proteins. In contrast, this detector does not respond to oxaliplatin adducts.
Br J Cancer 1999 Mar
PMID:Induction of JNK and c-Abl signalling by cisplatin and oxaliplatin in mismatch repair-proficient and -deficient cells. 1009 43

In human ovarian carcinomas, the p53 tumor-suppressor gene is frequently mutated. Interleukin-6 (IL-6) in these tumors is known to stimulate tumor-cell proliferation. In order to evaluate the effect of several p53 phenotypes on the IL-6 promoter activity, the human ovarian wild-type (wt)-p53 cell line A2780 was stably transfected with an empty plasmid (CMV) or (m)-175-, m-248- or m-273-p53. Electrophoretic mobility-shift assays revealed differences in activator protein-1 (AP-1) DNA-binding activity in the various clones. The CMV and m-273 clone had comparable amounts of AP-1. The m-175 clone displayed the least and m-248 the most pronounced AP-1 binding. Supershift analysis of AP-1/DNA complexes with antibodies against the AP-1 sub-units, c-Fos, FosB, Fra-1, Fra-2, c-Jun, JunB, and JunD, revealed that the AP-1/DNA complexes in the various clones had different compositions. Fra proteins were basically present only in m-175 and m-248 AP-1. IL-6-promoter activity was evaluated in the presence and absence of the AP-1 binding site which showed that the m-175-transfected clone has a transcriptional suppressing AP-1, whereas the CMV and the m-273 clones have an activating AP-1. Exposure of the p53 clones to tumor-necrosis factor-alpha (TNF-alpha) clearly altered the AP-1/DNA complex composition. IL-6-promoter activity was enhanced by TNF-alpha irrespective of the presence of an AP-1 binding site, while the degree of activation differed in the various clones, being most pronounced in the m-175 and m-248 clones. The results demonstrate that the basic and activated IL-6-promoter activity is differently regulated in the various p53 clones, possibly due to alterations in the AP-1 composition.
Int J Cancer 1999 Apr 12
PMID:Differential regulation of IL-6 promoter activity in a human ovarian-tumor cell line transfected with various p53 mutants: involvement of AP-1. 1018 25

The Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis and is implicated in the development of several human malignancies. Latent membrane protein 1 (LMP1), an EBV protein with known oncogenic properties, may be important in the pathogenesis of EBV-associated tumors, particularly nasopharyngeal carcinoma (NPC) and Hodgkin's disease (HD). Several reports suggested that sequence variations in the LMP1 gene may define a more aggressive, geographically restricted EBV-genotype. Most mutations in the LMP1 gene described are located within the C-terminus of the protein. However, the effect of these mutations on the biological function of the protein remains widely unknown. Therefore, this study aimed in investigating whether mutations detected in LMP1 genes isolated from different EBV-positive carriers have an effect on the biological function of the protein. For this purpose the LMP1 genes were amplified by nested PCR from DNA out of bone marrow and peripheral blood lymphocytes and sequenced. Three functional assays were performed in order to evaluate the biological activity of the different isolates: activation of the transcription factors NF-kappaB and AP-1 as well as the anchorage independent growth of LMP1 transfected ratl cells in soft agar. The results suggested that whereas differences in the activation of NF-kappaB through the various LMP1 isolates correlated tightly with their different expression levels, the outgrowth of transfected cells in soft agar did not and the transcription factor NF-kappaB therefore appeared not to be the major effector for the transformation of the rodent cell line ratl by LMP1. The various LMP1-isolates also differed in their capacity in activating the transcription factor AP-1. We found no correlation between the transforming ability of the LMPI isolates and activation of AP-1 suggesting that other so far uncharacterized domains also influence the transforming ability of the protein.
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PMID:Functional analysis of different LMP1 proteins isolated from Epstein-Barr virus-positive carriers. 1022 73

Mixed lineage kinases (MLKs) form a family of serin/threonine protein kinases with multiple protein/protein interaction domains (SH3, Cdc42 Rac interactive binding sequence, leucine zipper, and proline rich region), the physiological roles of which are largely unknown. We show that overexpression of wild type MLK3 leads to morphological transformation of NIH 3T3 fibroblasts and growth in soft agar. Consistent with this transforming potential, we demonstrate that MLK3 strongly induces transcription from a reporter construct that is driven by a composite AP-1-/Ets-1-enhancer element in HEK 293 cells. In the same cell system, MLK3 preferentially activates the c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) mitogen-activated protein kinase cascade and to a lesser degree the extracellular signal-regulated kinase (ERK) pathway. Activation of the latter can be further enhanced by coexpression of wild type MEK1 and is blocked by the synthetic MEK inhibitor PD 098059 or a kinase-dead MEK1 mutant. Immunoprecipitated MLK3 catalyses the phosphorylation of MEK1 in vitro, but this phosphorylation leads only to a marginal activation. In support of these data, we also show that MEK1 is highly phosphorylated in vivo on Ser 217/221 in MLK3-transformed fibroblasts, whereas activating ERK phosphorylations are barely detectable. Nevertheless, MLK3-transformed NIH 3T3 fibroblasts are partially reverted when activation of MEK is specifically blocked with PD 098059. Our combined data show that although MLK3 is primarily an activator of the JNK/SAPK pathway, overexpression of the wild type protein leads to a transformed phenotype in NIH 3T3 cells that can be partially reversed by a synthetic MEK inhibitor. We conclude that the ERK pathway is necessary for MLK3-mediated transformation.
Cancer Res 1999 May 01
PMID:The JNK/SAPK activator mixed lineage kinase 3 (MLK3) transforms NIH 3T3 cells in a MEK-dependent fashion. 1023 8

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.
Cancer Res 1999 May 15
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


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