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)

Alkyl-lysophospholipids (ALPs) represent a new class of antitumor drugs that induce apoptotic cell death in a variety of tumor cell lines. Although their precise mechanism of action is unknown, ALPs primarily act on the cell membrane, where they inhibit signaling through the mitogen-activated protein kinase (MAPK) pathway. Because stimulation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway is essential for radiation-induced apoptosis in certain cell types, we tested the effect of ALPs in combination with ionizing radiation on MAPK/SAPK signaling and apoptosis induction. Here, we present data showing that three ALPs, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine, hexadecylphosphocholine, and the novel compound octadecyl-(1,1-dimethyl-piperidinio-4-yl)-phosphate (D-21266) induce time- and dose-dependent apoptosis in the human leukemia cell lines U937 and Jurkat T but not in normal vascular endothelial cells. Moreover, in combination with radiation, ALPs strongly enhance the induction of apoptosis in both leukemic cell lines. All tested ALPs not only prevented MAPK activation, but, like radiation, stimulated the SAPK/JNK cascade within minutes. A dominant-negative mutant of c-Jun inhibited radiation- and ALP-induced apoptosis, indicating a requirement for the SAPK/JNK pathway. Our data support the view that ALPs and ionizing radiation cause an enhanced apoptotic effect by modulating the balance between the mitogenic, antiapoptotic MAPK, and the apoptotic SAPK/JNK pathways. This type of modulation of specific signal transduction pathways in tumor cells may lead to the development of new therapeutic strategies.
Cancer Res 1999 May 15
PMID:Alkyl-lysophospholipids activate the SAPK/JNK pathway and enhance radiation-induced apoptosis. 1034 58

Cisplatin treatment activates multiple signal transduction pathways, which can lead to several cellular responses including cell cycle arrest, DNA repair, survival, or apoptosis. We investigated the response of the mitogen-activated protein kinases, extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun-N-terminal kinase 1 (JNK1), and p38, to cisplatin treatment in the ovarian carcinoma cell line SK-OV-3. Cisplatin caused a late and prolonged induction in a dose-dependent manner of both ERK1/2 and JNK1 activity. ERK1/2 and JNK1 activities continued to increase in magnitude up to 24 h following initiation of cisplatin treatment. In contrast, cisplatin treatment had no effect on p38 activity. Transplatin failed to induce either ERK1/2 or JNK1 at 24 h, which suggests that the activation of these kinases was dependent on cisplatin-specific DNA damage. Treatment with cycloheximide resulted in inhibition of cisplatin-induced ERK1/2 activation, demonstrating that ERK1/2 activity induced by cisplatin was dependent on de novo protein synthesis. Furthermore, inhibition of cisplatin-induced ERK1/2 activity by PD 98059 caused enhanced cisplatin cytotoxicity. Similar enhanced cytotoxic effects of cisplatin were also observed following treatment with PD 98059 in the ovarian carcinoma cell line UCI 101. These observations indicate that ERK1/2 activation induced by cisplatin partially protects cells from cisplatin cytotoxicity. Continued investigation into the mechanism by which the ERK pathway and other signal transduction pathways modulate the response to cisplatin may be helpful in the development of new strategies for improving the therapeutic use of platinum drugs.
Clin Cancer Res 1999 May
PMID:Cisplatin-induced activation of mitogen-activated protein kinases in ovarian carcinoma cells: inhibition of extracellular signal-regulated kinase activity increases sensitivity to cisplatin. 1035 33

Activator protein 1 (AP-1) is a transcription factor which plays a critical role in inflammation and carcinogenesis. The present study was conducted to investigate the effect of berberine, an isoquinoline alkaloid present in plants of the genera Berberis and Coptis, on the activity of AP-1 using a reporter gene assay in human hepatoma cells. Berberine was shown to inhibit AP-1 activity in a dose- and time-dependent manner at concentrations higher than 0.3 microM. Berberine inhibited AP-1 activity almost completely as low as 10 microM after 48 h treatment. The inhibitory effect on AP-1 activity in cancer cells may further explain the anti-tumor promoting activity of berberine.
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PMID:Inhibition of activator protein 1 activity by berberine in human hepatoma cells. 1036 50

Arsenic has been used as an effective chemotherapy agent for some human cancers, such as acute promyelocytic leukemia. In this study, we found that arsenic induces activation of c-Jun NH2-terminal kinases (JNKs) at a similar dose range for induction of apoptosis in JB6 cells. In addition, we found that arsenic did not induce p53-dependent transactivation. Similarly, there was no difference in apoptosis induction between cells with p53 +/+ or p53 -/-. In contrast, arsenic-induced apoptosis was almost totally blocked by expression of a dominant-negative mutant of JNK1. These results suggest that the activation of JNKs is involved in arsenic-induced apoptosis of JB6 cells. Taken together with previous findings that p53 mutations are involved in approximately 50% of all human cancers and nearly all chemotherapeutic agents kill cancer cells mainly by apoptotic induction, we suggest that arsenic may be a useful agent for the treatment of cancers with p53 mutation.
Cancer Res 1999 Jul 01
PMID:Arsenic induces apoptosis through a c-Jun NH2-terminal kinase-dependent, p53-independent pathway. 1039 43

Although the precise role of oligosaccharides in metastasis is presently unknown, numerous studies suggest that the beta1-6 branching structure of N-linked oligosaccharides plays a role in tumor metastasis. N-Acetylglucosaminyltransferase V (GnT-V), which catalyzes the formation of the beta1-6 branch, therefore appears to play a crucial role in tumor metastasis. Recently, we demonstrated that the expression of the GnT-V gene is regulated by a transcriptional factor, Ets-1 (Kang, R., Saito, H., Ihara, Y., Miyoshi, E., Koyama, N., Sheng, Y., and Taniguchi, N. (1996) J. Biol. Chem. 271, 26706-26712). In this study, we report an investigation of the general requirement for Ets-1 in the expression of GnT-V in cancer cell lines. In 16 cancer cell lines, the levels of GnT-V mRNA were closely correlated with ets-1 expression (r = 0.97; p < 0.0001). An increase in ets-1 levels by transfection of its cDNA led to an enhancement in GnT-V expression in cells that normally expressed low levels of ets-1. In contrast, the transfection of dominant negative ets-1 into cells that express high levels of ets-1 resulted in a decrease in GnT-V expression. Although Ets-1 cooperates with c-Jun in certain gene expressions, this was not the case in the regulation of the GnT-V gene. These results suggest that Ets-1 plays a significant role in regulating the expression of GnT-V in a variety of cancers and might be involved in the potential for malignancy via the action of GnT-V.
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PMID:Regulation of the GnT-V promoter by transcription factor Ets-1 in various cancer cell lines. 1043 59

One of the characteristic responses of HT29 human colon adenocarcinoma cells to hypoxic stress is the induction of c-jun expression and binding to the activator-protein 1 (AP-1) element. To study the mechanism of c-jun activation during hypoxia, inhibitors of signaling pathways leading to the activation of AP-1 transcription factor were used. One of them, the benzoquinone ansamycin geldanamycin (GA) Mr-90,000 heat-shock protein (hsp90)-binding antibiotic, is known to disrupt signaling pathways by inducing destabilization of the enzyme complexes and degradation of signaling intermediates involving the proteasome. In our experiments, GA inhibited both basal and hypoxia-induced c-jun expression (IC50 = 75 nM). GA also abolished the hypoxia-induced increase in c-Jun NH2-terminal kinase (JNK1) catalytic activity and demonstrated an inhibitory effect on stress-activated protein kinase/ERK kinase-1 (SEK1); other participants in the mitogen-activated protein kinase and p38 signal transduction pathways were not affected to the same degree. GA treatment led to a decrease in the nuclear content of c-Jun but not that of c-Fos or of activating transcription factor 2. Functional consequences of these effects were suggested by the inhibition of AP-1 binding in hypoxic HT29 cells in the presence of GA. Pretreatment with the proteasome inhibitor lactacystin before the addition of GA resulted in the elevation of overall c-jun level, but it was unable to restore the hypoxia-induced c-jun expression. Our results demonstrate that GA acts as a highly potent inhibitor of hypoxia-induced c-jun expression, affecting the activation of JNK and of the AP-1 transcription factor. However, the effect of GA cannot be attributed solely to the inhibition of signaling through JNK, and additional mechanisms remain to be identified.
Cancer Res 1999 Aug 15
PMID:Effects of geldanamycin on signaling through activator-protein 1 in hypoxic HT29 human colon adenocarcinoma cells. 1046 87

The urokinase receptor, overexpressed in invasive colon cancer, promotes tumour cell invasion. Since K-Ras is activated in many colon cancers, we determined if urokinase receptor overexpression is a consequence of this activated oncogene. Accordingly, urokinase receptor expression was compared in HCT 116 colon cancer cells containing either a mutation-activated K-Ras or disrupted for this oncogene (by homologous recombination). HCT 116 cells containing the disrupted K-Ras oncogene expressed between 50 and 85% less urokinase receptor protein compared with the parental HCT 116 cells. Reduced urokinase receptor expression in cells containing the disrupted mutated K-Ras was not due to a physical impairment of the urokinase receptor gene since phorbol ester treatment was inductive for its expression. Constitutive urokinase receptor expression in HCT 116 cells required an intact AP-1 motif in the promoter (at -184) and electrophoretic mobility shifting assays indicated less c-Jun, JunD, c-Fos and Fra-1 bound to this motif in the K-Ras-disrupted cells. Since the urokinase receptor accelerates proteolysis, laminin degradation was compared in cells containing the mutation-activated and disrupted K-Ras oncogene. The latter cells displaying fewer urokinase receptors, degraded 80% less laminin. This is the first study to demonstrate a role for K-Ras as a regulator of the constitutive expression of the urokinase receptor.
Br J Cancer 1999 Aug
PMID:Targeted disruption of the K-ras oncogene in an invasive colon cancer cell line down-regulates urokinase receptor expression and plasminogen-dependent proteolysis. 1047 Oct 35

Estrogen receptor function can drive cyclin D1 expression and proliferation in human breast cancer cells (MCF-7). Recent studies showing that estrogen receptor-positive epithelial cells in the human mammary gland are nonproliferative suggest that the direct mitogenic effect of estrogen on mammary epithelial cells may be acquired during breast cancer development. Because estrogen-dependent cyclin D1 expression has been linked to its mitogenicity, we characterized the ability of estrogen to regulate cyclin D1 expression in estrogen receptor-negative breast cancer cells (MDA-MB-231) and nontransformed human keratinocytes (HaCaT) stably expressing the estrogen receptor. In both cases, estrogen receptor function did not induce cyclin D1 expression. Although MCF-7 cells respond to estrogen by inducing the AP-1 family components c-Fos and c-Jun, HaCaT cells expressing estrogen receptor do not. These results may explain the lack of estrogen-dependent cyclin D1 expression and proliferation in cells ectopically expressing the estrogen receptor. Therefore, estrogen receptor function alone is not sufficient for estrogen-dependent cyclin D1 expression and proliferation. Other transcriptional cofactors that allow estrogen receptor to induce expression of AP-1 may be required for estrogen to act as a mitogen.
Cancer Res 1999 Oct 01
PMID:Functional activity of ectopically expressed estrogen receptor is not sufficient for estrogen-mediated cyclin D1 expression. 1051 85

Microtubule inhibitors are widely used in cancer chemotherapy, but the signaling mechanisms that link microtubule disarray to destructive or protective cellular responses are poorly understood. Because members of the mitogen-activated protein kinase (MAPK) family have been implicated in regulation of cell survival and cell death, we examined the extent and kinetics of activation of JNK, ERK, and p38 MAPKs in response to treatment of KB-3 carcinoma cells with several microtubule inhibitors. All four agents tested (vinblastine, vincristine, Taxol, and colchicine) caused significant (6- to 13-fold) activation of JNK, concomitant inactivation of ERK, and a reduction in basal p38 MAPK activity. JNK activation and ERK inactivation occurred prior to caspase 3 activation. The microtubule inhibitors also induced phosphorylation of Raf-1 kinase. SEK-1, upstream of JNK, was also activated and phosphorylated in response to the microtubule inhibitors, and sustained phosphorylation of three endogenous JNK substrates (c-Jun, ATF-2, and JunD) was observed. By comparison, the antitumor agent doxorubicin induced activation of JNK and p38 but had no effect on ERK activity or Raf-1. These data demonstrate that microtubule inhibitors elicit distinct and specific effects on MAPK-mediated signaling pathways and suggest in particular that coordinate and reciprocal alterations in JNK and ERK activities are important facets of the cellular response to microtubule disruption.
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PMID:Microtubule inhibitors elicit differential effects on MAP kinase (JNK, ERK, and p38) signaling pathways in human KB-3 carcinoma cells. 1062 71

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.
Cancer Res 2000 Jan 15
PMID:A dominant role for the c-Jun NH2-terminal kinase in oncogenic ras-induced morphologic transformation of human lung carcinoma cells. 1066 94


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