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)

Smad proteins play a key role in the intracellular signaling of the transforming growth factor beta (TGF-beta) superfamily of extracellular polypeptides that initiate signaling to regulate a wide variety of biological processes. The inhibitory Smad, Smad7, has been shown to function as intracellular antagonists of TGF-beta family signaling and is upregulated in several cancers. To determine the effect of Smad7-mediated blockade of TGF-beta signaling, we have stably expressed Smad7 in a TGF-beta-sensitive, well-differentiated, and non-tumorigenic cell line, FET, that was derived from human colon adenocarcinoma. Smad7 inhibits TGF-beta-induced transcriptional responses by blocking complex formation between Smad 2/3 and Smad4. While Smad7 has no effect on TGF-beta-induced activation of p38 MAPK and ERK, it blocks the phosphorylation of Akt by TGF-beta and enhances TGF-beta-induced phosphorylation of c-Jun. FET cells expressing Smad7 show anchorage-independent growth and enhance tumorigenicity in athymic nude mice. Smad7 blocks TGF-beta-induced growth inhibition by preventing TGF-beta-induced G1 arrest. Smad7 inhibits TGF-beta-mediated downregulation of c-Myc, CDK4, and Cyclin D1, and suppresses the expression of p21(Cip1). As a result, Smad7 inhibits TGF-beta-mediated downregulation of Rb phosphorylation. Furthermore, Smad7 inhibits the apoptosis of these cells. Together, Smad7 may increase the tumorigenicity of FET cells by blocking TGF-beta-induced growth inhibition and by inhibiting apoptosis. Thus, this study provides a mechanism by which a portion of human colorectal tumors may become refractory to tumor-suppressive actions of TGF-beta that might result in increased tumorigenicity.
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PMID:Smad7 induces tumorigenicity by blocking TGF-beta-induced growth inhibition and apoptosis. 1592 43

Bortezomib is a highly selective, reversible inhibitor of the 26S proteasome that is indicated for single-agent use in the treatment of patients with multiple myeloma who have received at least 2 prior therapies and are progressing on their most recent therapy. Clinical investigations have been completed or are under way to evaluate the safety and efficacy of bortezomib alone or in combination with chemotherapy in multiple myeloma, both at relapse and presentation, as well as in other cancer types. The antiproliferative, proapoptotic, antiangiogenic, and antitumor activities of bortezomib result from proteasome inhibition and depend on the altered degradation of a host of regulatory proteins. Exposure to bortezomib has been shown to stabilize p21, p27, and p53, as well as the proapoptotic Bid and Bax proteins, caveolin-1, and inhibitor kappaB-alpha, which prevents activation of nuclear factor kappaB-induced cell survival pathways. Bortezomib also promoted the activation of the proapoptotic c-Jun-NH2 terminal kinase, as well as the endoplasmic reticulum stress response. The anticancer effects of bortezomib as a single agent have been demonstrated in xenograft models of multiple myeloma, adult T-cell leukemia, lung, breast, prostate, pancreatic, head and neck, and colon cancer, and in melanoma. In these preclinical in vivo studies, bortezomib treatment resulted in decreased tumor growth, angiogenesis, and metastasis, as well as increased survival and tumor apoptosis. In several in vitro and/or in vivo cancer models, bortezomib has also been shown to enhance the antitumor properties of several antineoplastic treatments. Importantly, bortezomib was generally well tolerated and did not appear to produce additive toxicities when combined with other therapies in the dosing regimens used in these preclinical in vivo investigations. These findings provide a rationale for further clinical trials using bortezomib alone or in combination regimens with chemotherapy, radiation therapy, immunotherapy, or novel agents in patients with hematologic malignancies or solid tumors.
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PMID:Preclinical evaluation of the proteasome inhibitor bortezomib in cancer therapy. 1592 91

Human glutamylcysteine ligase catalytic subunit (GCLC) is the rate-limiting enzyme for glutathione synthesis. The heavy subunit possesses all the catalytic activities. UV irradiation (UV-C, 30 J/m(2)) induced apoptosis in HEK293 cells, but the morphological changes were inhibited significantly by expression of GCLC. MTS assay and flow cytometry results also indicated that GCLC and JNK1(APF) expression enhanced cellular resistance to UV irradiation. Western blotting showed that irradiation strongly activated the c-Jun NH(2)-terminal kinases (JNKs) and caspase-3 as well as p38 in HEK293 cells. Interestingly, existing data show that GCLC blocks JNK1 phosphorylation but does not affect p38 phosphorylation. Therefore, overexpression of GCLC protected HEK293 cells against UV irradiation-induced cell death by inhibiting the phosphorylation and activation of JNK1, concomitantly with the inhibition of caspase-3 activation and p21(WAF1)-luciferase activity downstream of JNK.
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PMID:Human glutamylcysteine synthetase protects HEK293 cells against UV-induced cell death through inhibition of c-Jun NH2-terminal kinase. 1593 21

PRIMA-1 (p53 reactivation and induction of massive apoptosis) is a chemical compound that was originally identified as a selective mutant p53-dependent growth suppressor by screening a library of low-molecular-weight compounds. However, its mechanism of action is unknown. In this study, we examined toxicity of PRIMA-1 to three premalignant human colorectal adenoma cell lines (RG/C2, BR/C1, and AA/C1) and four colorectal carcinoma cell lines (DLD-1, SW480, LOVO, and HCT116) and its mechanism of action. It selectively induced apoptosis only in the mutant p53 premalignant and malignant colon cell lines, but was not toxic to the wild-type p53 premalignant and malignant colon cell lines. Using stable transfectants of temperature-sensitive p53 mutant Ala(143) in null p53 H1299 lung cancer cells, we found that PRIMA-1 induced significantly more apoptosis in cells with mutant p53 conformation (37 degrees C) than the wild-type p53 conformation (32.5 degrees C). Cell cycle analysis indicated that its inhibition of cell growth was correlated with induction of G(2) arrest. Western blot analysis showed PRIMA-1 increased p21 and GADD45 expression selectively in the mutant p53 cells. However, Fas, Bcl-2 family proteins, and caspases were not involved in PRIMA-1-induced cell death. The c-Jun-NH(2)-kinase (JNK) inhibitor SP 600125, but not p38 mitogen-activated protein kinase inhibitor SB 203580 or extracellular signal-regulated kinase inhibitor PD 98059, blocked PRIMA-1-induced apoptosis. Transfection with a dominant-negative phosphorylation mutant JNK, but not a dominant-negative p38 or wild-type JNK, inhibited PRIMA-1-induced cell death, suggesting that the JNK pathway plays an important role in PRIMA-1-induced apoptosis. PRIMA-1 is a highly selective small molecule toxic to p53 mutant cells and may serve as a prototype for the development of new p53-targeting agents for therapy of premalignant and malignant cells.
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PMID:Selective induction of apoptosis in mutant p53 premalignant and malignant cancer cells by PRIMA-1 through the c-Jun-NH2-kinase pathway. 1595 47

Changes in intracellular redox status are crucial events that trigger downstream proliferation or death responses through activation of specific signaling pathways. Moreover, cell responses to oxidative challenge may depend on the pattern of redox-sensitive molecular factors. The stress-activated protein kinases c-Jun-N-terminal kinase (JNK) and p38 MAP kinase (p38MAPK) are implicated in different forms of apoptotic neuronal cell death. Here, we investigated the effects, on neuroblastoma cells, of the prooxidant molecule GSSG, which we previously demonstrated to be an efficient proapoptotic compound able to activate the p38MAPK death pathway in promonocytic cells. We found that neuroblastoma cells are not prone to GSSG-induced apoptosis, although the treatment slightly induced growth arrest through the accumulation of p53 and its downstream target gene, p21. However, GSSG treatment became cytotoxic when cells were previously depleted of intracellular GSH content. Under this condition, apoptosis was triggered by an increased production of superoxide that led to a specific activation of the JNK-dependent pathway. The involvement of superoxide and JNK was demonstrated by cell death inhibition in experiments carried out in the presence of Cu,Zn superoxide dismutase or with specific inhibitors of JNK activity. Our data give support to the studies that indicate preferential requirements for the involvement of stress-activated kinases in apoptotic neuronal cells.
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PMID:Activation of c-Jun-N-terminal kinase is required for apoptosis triggered by glutathione disulfide in neuroblastoma cells. 1599 33

We recently reported that the ginseng saponin metabolite, compound K (20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol, IH901), inhibits the growth of U937 cells through caspase-dependent apoptosis pathway. In this study, we further characterized the effects of compound K on U937 cells and found that, in addition to apoptosis, compound K induced the arrest of the G1 phase. The compound K treated U937 cells showed increased p21 expression; an inhibitory protein of cyclin-cdk complex. The up-regulation of p21 was followed by the inactivation of cyclin D and the cdk4 protein, which act at the early G1 phase, and cyclin E, which acts at the late G1 phase. Furthermore, compound K induced the activation of JNK and the transcription factor AP-1, which is a downstream target of JNK. These findings suggest that the up-regulation of p21 and activation of JNK in the compound K treated cells contribute to the arrest of the G1 phase.
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PMID:G1 phase arrest of the cell cycle by a ginseng metabolite, compound K, in U937 human monocytic leukamia cells. 1604 78

The two distinct members of the mitogen-activated protein (MAP) kinase family c-Jun N-terminal protein kinase (JNK) and p38 MAP kinase, play an important role in central nervous system (CNS) development and differentiation. However, their role and functions are not completely understood in CNS. To facilitate in vitro study, we have established an immortal stem cell line using SV40 from fetal rat embryonic day 17. In these cells, MAP kinase inhibitors (SP600125, SB202190, and PD98059) were treated for 1, 24, 48, and 72 h to examine the roles of protein kinases. Early inhibition of JNK did not alter phenotypic or morphological changes of immortalized cells, however overexpression of Bax and decrease of phosphorylated AKT was observed. The prolonged inhibition of JNK induced polyploidization of immortalized cells, and resulted in differentiation and inhibition of cell proliferation. Moreover, JNK and p38 MAP kinase but not ERK1/2 was activated, and p21, p53, and Bax were overexpressed by prolonged inhibition of JNK. These results indicate that JNK and p38 MAP kinase could play dual roles on cell survival and apoptosis. Furthermore, this established cell line could facilitate study of the role of JNK and p38 MAP kinase on CNS development or differentiation/apoptosis.
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PMID:The role of p38 MAP kinase and c-Jun N-terminal protein kinase signaling in the differentiation and apoptosis of immortalized neural stem cells. 1604 26

Loss of susceptibility to apoptosis signals is a crucial step in carcinogenesis. Therefore, sensitization of tumor cells to apoptosis is a promising therapeutic strategy. c-Jun-N-terminal-kinases (JNK) have been implicated in stress-induced apoptosis, but may also contribute to survival signaling. Here we show that CD95-induced apoptosis is augmented by the JNK inhibitor SP600125 and small interfering RNA directed against JNK1/2. SP600125 potently inhibited methyl methane sulfonate-induced phosphorylation of c-Jun, but had minimal effect on apoptosis alone. In contrast, it strongly enhanced CD95-mediated apoptosis in six of eight tumor cell lines and led to a G2/M phase arrest in all cell lines. SP600125 enhanced cleavage of caspase 3 and caspase 8, the most upstream caspase in the CD95 pathway. JNK inhibition up-regulates p53 and its target genes p21Cip1/Waf1 and CD95. However, although HCT116 p53-/- cells and p21+/+ cells were less sensitive to CD95 stimulation than their p53+/+ and p21-/- counterparts, p53 and p21 were not involved in the JNK-mediated effect. JunD, which was described to be protective in tumor necrosis factor-induced apoptosis, was not regulated by JNK inhibition on the protein level. When transcription was blocked by actinomycin D, JNK inhibition still enhanced apoptosis to a comparable extent. We conclude that JNK inhibition has antitumor activity by inducing growth arrest and enhancing CD95-mediated apoptosis by a transcription-independent mechanism.
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PMID:Inhibition of c-Jun-N-terminal-kinase sensitizes tumor cells to CD95-induced apoptosis and induces G2/M cell cycle arrest. 1606 60

Reports elsewhere demonstrated that Epimedin C, a constituent isolated from the leaves of Epimedium sagittatum, possessed anti-tumor activity. However, its mechanism of action remains unresolved. Using SK-Hep-1 cells, a poorly-differentiated hepatoma subline, as an experimental model, we present evidence here that the anti-tumor activity of Epimedin C may involve cell cycle blockage. Immunoblotting analyses demonstrated that Epimedin C caused a decreased expression of hyperphosphorylated retinoblastoma (Rb) protein, cyclin D1, c-Myc, and c-Fos. In parallel, we measured the kinase activities and found that CDK2 and CDK4 were suppressed with commensurate increased levels of CDK inhibitors, p21(Cip1) and p27(Kip1). These data suggested that Epimedin C arrested the proliferation of these cells at G0/G1 phase through inhibition of CDK2 and CDK4 activities via an increased induction of p21(Cip1) and p27(Kip1). Alternatively, we investigated whether the anti-proliferative effect of Epimedin C on these cells might involve MAP kinase cascade. Using western blotting technique, we demonstrated that Epimedin C also selectively decreased ERK1/2 phosphorylation. Among the downstream effectors of ERK examined, we found that Epimedin C selectively decreased the expression of c-Fos, but not c-Jun. By EMSA assay, we further demonstrated that decreased c-Fos resulted in the downregulation of AP-1/DNA binding activity. Taken together, the molecular mechanisms of anti-tumor activity of Epimedin C may be proceeded by the combined effects of the cell cycle blockage via either the inhibition of CDK2 and CDK4 activities, with commensurate increase in their inhibitors, p21(Cip1) and p27(Kip1) or negatively modulates the ERK/c-Fos/AP-1 signaling pathway.
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PMID:Molecular mechanism of cell cycle blockage of hepatoma SK-Hep-1 cells by Epimedin C through suppression of mitogen-activated protein kinase activation and increased expression of CDK inhibitors p21(Cip1) and p27(Kip1). 1611 86

To investigate the apoptosis induced by manganese (Mn) in hepatocytes in vivo, rats received a single injection of manganese chloride immediately after partial hepatectomy. Characteristic DNA fragmentation was observed at 4 h after partial hepatectomy with Mn-injection. The activation of caspase-3 by Mn-injection was detected as early as 30 min and peaked at 1 h after partial hepatectomy. The activity of Jun N-terminal kinase (JNK) increased to a maximal level, which was about 10-fold the maximal level of the control, at 15 min after partial hepatectomy and this increase was maintained for 4 h in Mn-injected rats, while a transient increase was observed at 1 h in the control. No effect of the Mn-injection on the activation of p38 mitogen-activated protein kinase (MAPK) was observed. Western blot analysis revealed that the injection of Mn markedly increased c-Jun and phosphorylated c-Jun protein levels at 1 h after partial hepatectomy. An increase in p53 was also observed at 30 min after the Mn-injection and followed by the upregulation of p21(WAF1/CIP1) protein expression at 2 h after partial hepatectomy. These results suggested that the activation of JNK and the upregulation of c-Jun, p53 and p21(WAF1/CIP1) were involved in the apoptosis of hepatocytes induced by partial hepatectomy with manganese.
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PMID:Manganese-induced apoptosis in hepatocytes after partial hepatectomy. 1629 43


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