Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T-cadherin is an atypical cadherin and growing evidence has indicated that T-cadherin exerts tumor-suppressive effects on cancers of epithelial cell type and also causes positive effects on tumor angiogenesis. Human hepatocellular carcinoma (HCC) is a hypervascular tumor and T-cadherin has been shown to be overexpressed in intratumoral endothelial cells of HCCs. However, the expression status and functions of T-cadherin in hepatocytes or HCC cells remain unclear. Here, we demonstrated that T-cadherin was underexpressed in HCC cells (26.5%, 13/49 cases), but was frequently (77.6%, 38/49) overexpressed in intratumoral endothelial cells immunohistochemically. Semiquantitative RT-PCR analysis also showed that the T-cadherin gene was underexpressed in 7 of 11 HCC cell lines. Loss of heterozygosity analysis revealed that 32-38% of the 42 human HCC samples had allelic losses at this locus. Upon pharmacological treatment with demethylating agent 5-aza-2'-deoxycytidine or histone deacetylase inhibitor trichostatin A, T-cadherin promoter hypermethylation and/or histone deacetylation was frequently observed in HCC samples and cell lines. Functionally, enforced expression of T-cadherin induced G(2)/M cell cycle arrest, reduced cell proliferation in low serum medium, suppressed anchorage-independent growth in soft agar and increased sensitivity to TNFalpha-mediated apoptosis in HCC cells. Intriguingly, we found that T-cadherin significantly suppressed the activity of c-Jun, a crucial oncoprotein constitutively activated in HCC cells. To conclude, T-cadherin was differentially expressed in human HCCs. The underexpression of T-cadherin in HCC cells suggests it may be another critical event in addition to T-cadherin-mediated angiogenesis during HCC development.
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PMID:Genetic and epigenetic inactivation of T-cadherin in human hepatocellular carcinoma cells. 1855 87

The mechanism by which the histone deacetylase (HDAC) inhibitor trichostatin A inhibits epidermal growth factor (EGF)-induced human 12(S)-lipoxygenase expression was studied. Trichostatin A treatment of human epidermoid carcinoma A431 cells inhibited the EGF-induced 12(S)-lipoxygenase enzymatic activity in a dose-dependent manner that was consistent with the expression of 12(S)-lipoxygenase mRNA and protein. Confocal microscopy indicated that trichostatin A treatment of cells resulted in downregulation of EGF-induced c-Jun expression. Western blotting revealed that trichostatin A treatment of cells resulted in downregulation of EGF-induced c-Jun and constitutively Sp1 expression. Results of a chromatin immunoprecipitation assay revealed that trichostatin A treatment of cells also upregulated Sp1 acetylation and attenuated the recruitment of Sp1, c-Jun, and p300 to the 12(S)-lipoxygenase gene promoter. These results suggested that trichostatin A inhibited EGF-induced 12(S)-lipoxygenase expression by multiple mechanisms, including the attenuation of c-Jun and Sp1 expression and p300 recruitment to the 12(S)-lipoxygenase gene promoter.
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PMID:Attenuation of c-Jun and Sp1 expression and p300 recruitment to gene promoter confers the trichostatin A-induced inhibition of 12(S)-lipoxygenase expression in EGF-treated A431 cells. 1859 Jul 21

c-JUN is a major component of heterodimer transcription factor AP-1 (Activator Protein-1) that activates gene transcription in cell proliferation, inflammation and stress responses. SIRT1 (Sirtuin 1) is a histone deacetylase that controls gene transcription through modification of chromatin structure. However, it is not clear if SIRT1 regulates c-JUN activity in the control of gene transcription. Here, we show that SIRT1 associated with c-JUN in co-immunoprecipitation of whole cell lysate, and inhibited the transcriptional activity of c-JUN in the mammalian two hybridization system. SIRT1 was found in the AP-1 response element in the matrix metalloproteinase-9 (MMP9) promoter DNA leading to inhibition of histone 3 acetylation as shown in a ChIP assay. The SIRT1 signal was reduced by the AP-1 activator PMA, and induced by the SIRT1 activator Resveratrol in the promoter DNA. SIRT1-mediaetd inhibition of AP-1 was demonstrated in the MMP9 gene expression at the gene promoter, mRNA and protein levels. In mouse embryonic fibroblast (MEF) with SIRT1 deficiency (SIRT1(-/-)), mRNA and protein of MMP9 were increased in the basal condition, and the inhibitory activity of Resveratrol was significantly attenuated. Glucose-induced MMP9 expression was also inhibited by SIRT1 in response to Resveratrol. These data consistently suggest that SIRT1 directly inhibits the transcriptional activity of AP-1 by targeting c-JUN.
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PMID:Inhibition of transcriptional activity of c-JUN by SIRT1. 1882 44

In light of the anti-inflammatory properties of histone deacetylase (HDAC) inhibitors, such as suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), we examined a new HDAC inhibitor KBH-A42 for its anti-inflammatory activities. KBH-A42 showed noteworthy anti-inflammatory properties in vitro via suppression of the production of TNF-alpha, a proinflammatory cytokine, and nitric oxide (NO), a proinflammatory effector molecule, in LPS-stimulated RAW264.7 cells and peritoneal macrophages. It also inhibited TNF-alpha production in vivo as demonstrated in a LPS-induced mouse endotoxemia model. The levels of TNF-alpha, IL-1beta, IL-6 and iNOS mRNAs determined by RT-PCR propose that the inhibition of these pro-inflammatory mediators by KBH-A42 resulted from inhibiting expression of these genes. However, the EMSA study to see the effect of KBH-A42 on the binding of NF-kappaB, a transcription factor, to a specific DNA sequence showed that the binding of NF-kappaB to DNA was not changed regardless of increasing the concentration of KBH-A42 in the presence and absence of LPS stimulation. Interestingly, DNA binding of another transcription factor AP-1 dose-dependently increased by KBH-A42. KBH-A42 differentially regulated the phosphorylation of MAP kinases. While the phosphorylation of ERK1/2 and SAPK/JNK was not affected by KBH-A42, the phosphorylation of p38 decreased by KBH-A42. These results showed that KBH-A42 inhibits production of proinflammatory cytokines in macrophages by decreasing their mRNA levels, and p38 kinase is involved in the KBH-A42-mediated inhibition.
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PMID:Histone deacetylase inhibitor KBH-A42 inhibits cytokine production in RAW 264.7 macrophage cells and in vivo endotoxemia model. 1898 16

The constitutively active Bcr-Abl tyrosine kinase plays a crucial role in chronic myelogenous leukemia (CML) pathogenesis. The Bcr-Abl protein induces the upregulation of proto-oncogene c-Jun, which is involved in Bcr-Abl transforming activity in Bcr-Abl positive cells. Recent studies reported that c-Jun inhibited hemoglobin synthesis in human CML cell line K562. However, c-Jun also plays a critical role in cell proliferation and apoptosis. In this study, we investigated the physiological roles of c-Jun in cell proliferation, apoptosis and erythroid differentiation of K562 cells. Firstly, we generated K562 cell lines stably overexpressing c-Jun. These clones have the same proliferation rate as the parental cell line in general culture medium. Endogenous c-Jun expression was analyzed to determine the effective concentration of STI571 for inhibiting Bcr-Abl signaling. Western blots show that STI571 inhibited c-Jun expression in a dose-dependent manner, reaching a maximum inhibition at 1 microM. STI571 could inhibit c-Jun expression in K562 cells, but not in c-Jun-overexpression cells. c-Jun did not alter growth inhibition and apoptotic induction by STI571 treatment, but inhibited STI571-induced erythroid differentiation. Moreover, c-Jun did not alter growth inhibition and apoptotic induction by histone deacetylase (HDAC) inhibitors (apicidin, sodium butyrate, and MS275) treatment, but inhibited HDAC inhibitors-induced erythroid differentiation. These results suggest that c-Jun may modulate anticancer drugs-induced cell differentiation but not growth inhibition and apoptosis in CML cells.
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PMID:c-Jun blocks cell differentiation but not growth inhibition or apoptosis of chronic myelogenous leukemia cells induced by STI571 and by histone deacetylase inhibitors. 1900 73

Matrix metalloproteinase (MMP)-1 promotes ultraviolet (UV)-triggered long-term detrimental effects such as cancer formation and premature skin aging. Although histone modifications may play a crucial role in the transcriptional regulation of MMP-1, the relationship between UV-induced histone modification and MMP-1 expression is not completely understood. Here, we identify regulators of histone acetylation that may link UV-mediated DNA damage and MMP-1 induction by UV in cultured human dermal fibroblasts (HDFs) in vitro. UV irradiation of HDFs induced MMP-1 expression and increased the level of phosphorylation of H2AX (gamma-H2AX), p53 and the acetylation of histone H3 (acetyl-H3). Total histone deacetylase (HDAC) enzymatic activity was decreased by UV irradiation, while histone acetyltransferase (HAT) activity was increased. Suppression of p300 histone acetyltransferase (p300HAT) activity by the p300HAT inhibitor anacardic acid (AA) or by down-regulation of p300 by siRNA prevented UV-induced MMP-1 expression and inhibited UV-enhanced gamma-H2AX, p53 level, and acetyl-H3. Using chromatin immunoprecipitation assays, we observed that gamma-H2AX, p53, acetyl-H3, p300 and c-Jun were consistently recruited by UV to a distinct region (-2067/-1768) adjacent to the p300 binding site (-1858/-1845) in the MMP-1 promoter. In addition, these recruitments of gamma-H2AX, p53, acetyl-H3, p300 and c-Jun to the p300-2 site were significantly abrogated by post-treatment with AA. Furthermore, overexpression of p300 increased the basal and UV-induced MMP-1 promoter activity. Our results suggest that p300HAT plays a critical role in the transcriptional regulation of MMP-1 by UV.
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PMID:The role of p300 histone acetyltransferase in UV-induced histone modifications and MMP-1 gene transcription. 1928 85

We examined the interaction between the multikinase inhibitor sorafenib and histone deacetylase inhibitors. Sorafenib and vorinostat synergized (sorafenib + vorinostat) to kill HCT116 and SW480 cells. In SW480 cells, sorafenib + vorinostat increased CD95 plasma membrane levels and promoted death-inducing signal complex (DISC) formation, and drug toxicity was blocked by knockdown of CD95 or overexpression of cellular FLICE-like inhibitory protein (c-FLIP-s). In SW620 cells that are patient-matched to SW480 cells, sorafenib + vorinostat toxicity was significantly lower, which correlated with a lack of CD95 activation and lower expression of ceramide synthase 6 (LASS6). Overexpression of LASS6 in SW620 cells enhanced drug-induced CD95 activation and enhanced tumor cell killing, whereas knockdown of LASS6 in SW480 cells suppressed CD95 activation. Knocking down LASS6 expression also suppressed CD95 activation in hepatoma, pancreatic, and ovarian cancer cells. In HCT116 cells, sorafenib + vorinostat treatment caused DISC formation without reducing c-FLIP-s expression and did not increase CD95 plasma membrane levels; sorafenib + vorinostat exposure killed HCT116 cells via an intrinsic pathway/caspase 9-dependent mechanism. In HCT116 cells, knockdown of CD95 enhanced sorafenib + vorinostat lethality, which correlated with less drug-induced CD95-dependent autophagy. Sorafenib + vorinostat treatment activated the c-Jun NH(2)-terminal kinase pathway, which was causal in promoting dissociation of Beclin1 from BCL-2, and in promoting autophagy. Knockdown of Beclin1 expression blocked autophagy and enhanced drug toxicity. Our data demonstrate that treatment of colon cancer cells with sorafenib + vorinostat activates CD95 via de novo ceramide synthesis that promotes viability via autophagy or degrades survival via either the extrinsic or intrinsic pathways.
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PMID:Sorafenib and vorinostat kill colon cancer cells by CD95-dependent and -independent mechanisms. 1948 4

Kruppel-like factor 4 (KLF4) belongs to a family of evolutionarily conserved zinc finger-containing transcription factors. It has been shown to mediate self renewal and pluripotency, regulate adipogenesis and play a critical role in monocyte differentiation. KLF4 is also highly expressed in squamous cell carcinomas and in 70% of all primary human breast cancers, suggesting a putative role for KLF4 as being an oncogene and as an antiapoptotic factor. However, the mechanism of this regulation remains unclear. Here, we show that KLF4 is induced during histone deacetylase inhibitor treatment, and regulates the extrinsic apoptosis pathway by inhibiting caspase cleavage. In addition, KLF4 binds to the p57(Kip2) promoter and transcriptionally upregulates its expression, which in turn inhibits the stress activated protein kinase cascade and c-Jun phosphorylation. Our findings indicate that in cancer cells that express high levels of KLF4 may be refractory to HDACi treatment. Results of our study demonstrate an unexpected antiapoptotic function of KLF4, and suggest an important cell fate determinant following histone deacetylase inhibitor induced apoptosis.
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PMID:KLF4 suppresses HDACi induced caspase activation and the SAPK pathway by targeting p57(Kip2). 1954 95

Although many self-reactive T cells are eliminated by negative selection in the thymus, some of these cells escape into the periphery, where they must be controlled by additional mechanisms. However, the molecular mechanisms underlying peripheral T cell tolerance and its maintenance remain largely undefined. In this study, we report that sirtuin 1 (Sirt1), a type III histone deacetylase, negatively regulates T cell activation and plays a major role in clonal T cell anergy in mice. In vivo, we found that loss of Sirt1 function resulted in abnormally increased T cell activation and a breakdown of CD4+ T cell tolerance. Conversely, upregulation of Sirt1 expression led to T cell anergy, in which the activity of the transcription factor AP-1 was substantially diminished.Furthermore, Sirt1 interacted with and deacetylated c-Jun, yielding an inactive AP-1 factor. In addition, Sirt1-deficient mice were unable to maintain T cell tolerance and developed severe experimental allergic encephalomyelitis as well as spontaneous autoimmunity. These findings provide insight into the molecular mechanisms of T cell activation and anergy, and we suggest that activators of Sirt1 may be useful as therapeutic agents for the treatment and/or prevention of autoimmune diseases.
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PMID:The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice. 1972 33

Preliminary therapeutic successes have prompted a new wave of clinical trials enrolling patients with myelodysplastic syndromes (MDS), using compounds with a broad range of potential mechanisms of action. This article discusses several of the agents currently in development for MDS, reviewing clinical trial data related to five classes of novel therapeutics: clofarabine, a halogenated purine nucleoside analog; ezatiostat (TLK199), a glutathione analog that indirectly activates c-Jun kinase; tipifarnib, a farnesyltransferase inhibitor; laromustine (cloretazine), an alkylating agent with a metabolite that inhibits one mechanism of DNA damage repair; and eight drugs that inhibit histone deacetylase. Although MDS are still difficult clinical problems, and most patients with MDS still succumb to disease-related complications within 3 to 5 years of diagnosis, ongoing development of novel agents promises that there will be new treatment options for patients within the next 5 to 10 years.
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PMID:Novel therapies for myelodysplastic syndromes. 2035 35


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