Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Nuclear factor kappaB (NF-kappaB) and activator protein 1 are transcription factors involved in the regulation of cell proliferation that play important roles in tumorigenesis. We investigated whether these two factors cooperate for transcriptional regulation of cyclin D1 (CCND1), a gene whose deregulation is critical during carcinogenesis. We demonstrate that overexpression of JunD in human hepatocarcinoma cells strongly activates transcription mediated by the kappaB2 site of the CCND1 promoter in reporter assays, in a manner strictly dependent on the presence of NF-kappaB proteins. Serum stimulation increased the expression of p65, p50, c-Fos, c-Jun and JunD and induced the recruitment of p65, p50 and JunD to the kappaB2 site of the promoter in DNA pull-down assays. Chromatin immunoprecipitation (ChIP) analysis confirmed the serum-induced recruitment of JunD to the promoter in vivo and showed that the presence of JunD was dependent on the presence of p65 and p50, indicating a protein-protein-dependent mechanism of JunD recruitment. Serum-induced activation of protein binding to kappaB2 correlated with high levels of phosphoinositide-dependent protein kinase-1 (PDK-1) phosphorylation. Both LY294002, a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), and overexpression of a dominant-negative form of PDK-1 inhibited the JunD-stimulating effect in reporter assays. LY294002 also prevented the serum-induced recruitment of JunD, but not p65 or p50 to the promoter in ChIP assay. JunD-p65 complexes, identified in vivo by co-immunoprecipitation, were decreased by LY294002 and by small interfering RNA inhibition of PDK-1. Taken together, our data demonstrate a PI3K/PDK-1-dependent functional cooperation of NF-kappaB and JunD in the transcriptional regulation of CCND1 by serum.
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PMID:Jun D cooperates with p65 to activate the proximal kappaB site of the cyclin D1 promoter: role of PI3K/PDK-1. 1817 38

Etk/Bmx is a cytoplasmic tyrosine kinase, which was first identified in human bone marrow cells. It has been found to play an important role in the regulation of differentiation and tumorigenicity in some cancers. The aim of this study was to investigate the significance of Etk/Bmx expression in hepatocellular carcinoma (HCC) and the relationship between Etk/Bmx and activated protein-1 (AP-1)- and nuclear factor-kappaB (NF-kappaB)-associated proteins. We used immunohistochemisty to examine 40 cases of human HCC along with corresponding nontumor tissues to assess Etk/Bmx, Jun family (c-Jun, JunB, JunD), Fos family (c-Fos, FosB, Fra-1) and NF-kappaB p65 expression in these samples. Etk/Bmx expression was present in 12 of 40 (30%) HCC specimens, 4 of which among the 25 well-differentiated tumors and 8 among the 15 poorly differentiated tumors, respectively. In contrast, 6 of 40 (15%) cases expressed Etk/Bmx in adjacent nontumor tissues. Expression level and cellular localization of Etk/Bmx were different in cancer cells and nontumor cells. Etk/Bmx expression was correlated with histological differentiation, but not with clinicopathological features including tumor size, HBV infection, cirrhosis, and metastasis. There was a close relationship between Etk/Bmx and c-Fos expression in HCC. Etk/Bmx immunopositivity was independent of c-Jun, JunD, FosB, Fra-1 and NF-kappaB p65. Our results indicated that Etk/Bmx may have different biological roles in tumor and nontumor cells, and may be involved in regulating hepatocyte differentiation by c-Fos activation in HCC.
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PMID:Expression of tyrosine kinase Etk/Bmx and its relationship with AP-1- and NF-kappaB-associated proteins in hepatocellular carcinoma. 1819 28

The kringle 1 domain of human hepatocyte growth factor (HGFK1) was previously shown to inhibit bovine aortic endothelial cell proliferation, suggesting that it might be an antiangiogenic molecule. Here, we evaluated the in vivo efficacy of a recombinant adenoassociated virus carrying HGFK1 (rAAV-HGFK1) for the treatment of hepatocellular carcinoma (HCC) in a rat orthotopic HCC model and explored its molecular mechanisms in vitro in both endothelial and tumor cells. We first showed that rAAV-HGFK1 treatment significantly prolonged the survival time of rats transplanted with tumor cells. Treatment with rAAV-HGFK1 inhibited tumor growth, decreased tumor microvessel density, and completely prevented intrahepatic, lung, and peritoneal metastasis in this in vivo model. In vitro, rAAV-HGFK1 exhibited both antiangiogenic and antitumor cell effects, inhibiting the proliferation of both murine microvascular endothelial cells (MEC) and tumor cells, and inducing apoptosis and G(0)-G(1) phase arrest in these cells. To our surprise, rAAV-HGFK1 did not act through the hepatocyte growth factor/hepatocyte growth factor receptor pathway. Instead, it worked mainly through epidermal growth factor (EGF)/epidermal growth factor receptor (EGFR) signaling, with more minor contributions from vascular endothelial growth factor/vascular endothelial growth factor receptor and beta fibroblast growth factor (bFGF)/beta fibroblast growth factor receptor (bFGFR) signaling. In both MECs and tumor cells, rAAV-HGFK1 acted through two pathways downstream of EGFR, namely inhibition of extracellular signal-regulated kinase activation and stimulation of p38 mitogen-activated protein kinase/c-Jun-NH(2)-kinase activation. These results suggest for the first time that HGFK1 exerts both antiangiogenic and antitumor cell activities mainly through EGF/EGFR signaling, and may thus be considered as a novel therapeutic strategy for the treatment of HCC.
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PMID:The kringle 1 domain of hepatocyte growth factor has antiangiogenic and antitumor cell effects on hepatocellular carcinoma. 1819 34

The discovery of "ground glass" hepatocytes (GGH) that contain hepatitis B virus (HBV) surface antigens by Hadziyannis and Popper in 1973 represents a historical landmark in the pathology of chronic HBV infection. Different types of GGH have been correlated to the expression patterns of surface/core antigens and the stages of virus replication. The original two types (designated types I & II) of GGH were found to contain specific pre-S mutants with deletions over either pre-S1 or pre-S2 regions, respectively. Type II GGH consistently harbor pre-S2 deletion mutants, which can escape from immune attack and grow preferentially to form clusters. Both types of pre-S mutants can induce endoplasmic reticulum (ER) stress and oxidative DNA damage. The pre-S2 mutants, albeit inducing a weaker level of ER stress signals, could additionally initiate ER stress-independent retinoblastoma/adenovirus E2 promoter binding factor/cyclin A signaling through their interaction with c-Jun activation domain binding protein 1 to degrade p27, illustrating the growth advantage of type II GGH. The combined effects of genomic instability and the proliferation of hepatocytes harboring pre-S mutants could potentially lead to hepatocarcinogenesis over the decades of chronic HBV infection. The presence of pre-S mutants in sera was reported to carry a high risk of developing hepatocellular carcinoma (HCC). Furthermore, transgenic mice harboring pre-S2 mutant plasmids have been shown to develop a dysplastic change of hepatocytes and HCC. Therefore, in addition to being a histological marker of chronic HBV infection, GGH, particularly type II GGH, may represent the preneoplastic lesions of HBV-related HCC.
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PMID:Ground glass hepatocytes contain pre-S mutants and represent preneoplastic lesions in chronic hepatitis B virus infection. 1850 13

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

Several Ap1-like cis-acting elements were found within 5'-regulatory region (-2497...+173 versus transcription start point) of human apolipoprotein A-I gene (5'-apoA-I). Those elements are capable to interact with transcription factors belonging to Ap1 and CREB/ATF families. Those elements are localized outside of the hepatic enhancer (-220...-110) and the sequence responsible for apoA-I gene transcription in Caco2 cells (-595...-192). One of Ap1-like sites (5'-TGAGGTCT-3, Cre/jun2/apo) is present within 5'-apoA-I in two copies - distal (-1798 ...-1791) and proximal (+99...+106) ones. This and other Ap1-like sites - 5'-TGACTCT-3' (-1798...-1791, PF1) and 5'-TGACATCA-3' (-1171...-1163, Cre/jun1) were characterized by EMSA. It was shown by using the specific antibodies to c-Jun and ATF2 transcription factors in EMSA supershift experiments, that the DNA-protein complexes formed by Cre/jun2/apo, Cre/jun1 elements with nuclear proteins of human hepatoma HepG2 cells contain ATF2. The functional role of 5'-apoA-I regions containing Ap1-like sites was studied in cotransfection experiments of HepG2 cells (synthesize endogenous ApoA-I), human duodenum adenocarcinoma Hutu80 cells (do not synthesize endogenous ApoA-I), human neuroblastoma SK-N-SH cells (do not synthesize endogenous A-I) with expression vectors of c-jun and mekk1 genes. It was shown, that those Ap1-like sites appears to be responsible (the proximal Cre/jun2/apo is more efficient) for tissue-specific regulation of human apoA-I gene expression.
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PMID:[Ap1-like cis-elements in 5'-regulatory region of human apolipoprotein A-I gene]. 1861 Aug 38

Deregulation of cell cycle leads to cell transformation and cancer development. Here we present profiling the proteome dynamics using 2-DE and constructing the associated functional networks during the cell cycle of human hepatoma cells, Mahlavu. The protein dynamics was validated by hierarchical clustering analysis on the proteome, and by Northern blot assays on the selected 14-3-3 proteins. Of the 2665 protein spots, 201 with variation coefficient of expression dynamics >20% throughout the cell cycle were subjected to analysis. Degree of the global protein dynamics was phase dependent with the greatest in transitional phases of S/G2, G2/M, and G1/S. Concurrence of pathways coordinating cell-cycle progression versus arrest, and/or pathways regulating apoptosis versus antiapoptosis was always identified during the cell cycle, suggesting the existence of counteracting mechanisms for intracellular homeostasis. Data mining of the results suggested that the key transcription factors in G0/G1, G1/S, S, and G2/M were p53 and SP1, c-Myc, c-Myc and p53, and YY1 and c-Jun, respectively. Our findings for the first time provide insights into the regulation of mammalian cell-cycle progression at the proteome level, and grant a model to study disease mechanisms and to discover therapeutic targets for anticancer therapy.
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PMID:Profiling the proteome dynamics during the cell cycle of human hepatoma cells. 1865 25

Hepatocellular carcinoma (HCC) displays a striking resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Therefore, the characterization of pharmacological agents that overcome this resistance may provide new therapeutic modalities for HCC. Here, we examined whether glycogen synthase kinase-3 (GSK-3) inhibitors could restore TRAIL sensitivity in hepatoma cells. To this aim, the effects of two GSK-3 inhibitors, lithium and SB-415286, were analyzed on TRAIL apoptotic signaling in human hepatoma cell lines in comparison with normal hepatocytes. We observed that both inhibitors sensitized hepatoma cells, but not normal hepatocytes, to TRAIL-induced apoptosis by enhancing caspase-8 activity and the downstream recruitment of the mitochondrial machinery. GSK-3 inhibitors also stabilized p53 and the down-regulation of p53 by RNA interference abolished the sensitizing effect of lithium on caspase-3 activation. Concomitantly, GSK-3 inhibitors strongly activated c-Jun N-terminal kinases (JNKs). The pharmacological inhibition of JNKs with AS601245 or SP600125 resulted in an earlier and stronger induction of apoptosis indicating that activated JNKs transduced protective signals and provided an anti-apoptotic balance to the pro-apoptotic effects of GSK-3 inhibitors. These findings demonstrate that GSK-3 exerts a negative and complex constraint on TRAIL apoptotic signaling in hepatoma cells, which can be greatly alleviated by GSK-3 inhibitors. Therefore, GSK-3 inhibitors may open new perspectives to enhance the anti-tumor activity of TRAIL in HCC.
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PMID:Glycogen synthase kinase-3 inhibitors augment TRAIL-induced apoptotic death in human hepatoma cells. 1893 43

This study is the first to investigate the anticancer effect of dehydrocostuslactone [DHE (3aS,6aR,9aR,9bS)-decahydro-3,6,9-tris(methylene) azuleno[4,5-b]furan-2(3H)-one)], a medicinal plant-derived sesquiterpene lactone, on hepatocellular carcinoma. Our results showed that DHE inhibits the proliferation of HepG2 and PLC/PRF/5 cells by inducing apoptosis. DHE induces up-regulation of Bax and Bak, down-regulation of Bcl-2 and Bcl-XL, and nuclear relocation of the mitochondrial factors apoptosis-inducing factor (AIF) and endonuclease G (Endo G). DHE triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosol-calcium levels, double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase phosphorylation, inositol-requiring protein 1 (IRE1) and CHOP/GADD153 up-regulation, X-box transcription factor-1 mRNA splicing, and caspase-4 activation. Enhancement of ER stress by DHE is through p38 and extracellular signal-regulated kinase 1/2-dependent manners and subsequently causes c-Jun NH(2)-terminal kinase activation, resulting in AIF and Endo G nuclear relocation. Both of IRE1 small interfering RNA transfection and 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester pretreatment inhibit DHE-mediated apoptosis, supporting the hypothesis that DHE induces cell death through ER stress. It is noteworthy that animal studies have revealed a dramatic 50% reduction in tumor volume after 45 days of treatment. This study demonstrates that DHE may be a novel anticancer agent for the treatment of liver cancer.
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PMID:Dehydrocostuslactone, a medicinal plant-derived sesquiterpene lactone, induces apoptosis coupled to endoplasmic reticulum stress in liver cancer cells. 1918 81

Hepatic apoptosis is elevated in patients with non-alcoholic steatohepatitis and is correlated with the severity of the disease. Long-chain saturated fatty acids, such as palmitate, induce apoptosis in liver cells. The present study examined adiponectin-mediated protection against saturated fatty acid-induced apoptosis in the human hepatoma cell line, HepG2. Cells were cultured in a control media (i.e. without fatty acids) or the same media containing 250 micromol L(-1) of albumin-bound oleate or palmitate for 24 h. The adiponectin concentrations used were: 0, 1, 10 or 100 microg mL(-1) (n = 4-6 per treatment). Palmitate and thapsigargin, but not oleate, activated caspase-3 and decreased cell viability in the absence of adiponectin. Adiponectin reduced palmitate- and thapsigargin-induced activation of caspase-3 and cell death in a dose-dependent manner. Phosphatidylinositol 3-kinase and AMP-activated protein kinase inhibitors abolished the effects of adiponectin. Adiponectin-induced inhibition of palmitate- and thapsigargin-induced apoptosis was not the result of an augmentation in the unfolded protein response or the increased expression of genes encoding the inhibitor of apoptosis proteins, inhibitor of apoptosis protein-2 and X-linked mammalian inhibitor of apoptosis protein. Palmitate and thapsigargin, but not oleate, increased c-Jun NH(2) terminal kinase phosphorylation in the absence of adiponectin. Adiponectin blocked palmitate- and thapsigargin-induced activation of c-Jun NH(2) terminal kinase and reduced apoptosis. These data suggest that adiponectin is an important determinant of saturated fatty acid-induced apoptosis in liver cells and may have implications for fatty acid-mediated liver cell injury in adiponectin-deficient individuals.
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PMID:Full-length adiponectin protects hepatocytes from palmitate-induced apoptosis via inhibition of c-Jun NH2 terminal kinase. 1929 Aug 87


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