Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein expression of the retinoblastoma (Rb) tumor suppressor gene product was examined by immunoblot analysis of nuclei isolated from regenerating rat liver after 70% partial hepatectomy (PH). Levels were almost undetectable in quiescent 0-h livers but increased 15- to 60-fold 3 to 24 h post-PH, 105-fold at 30 h, and 20- to 50-fold at 60 to 72 h post-PH. Expression returned to near baseline levels at 18, 42, and 48 h post-PH. A similar pattern of Rb protein expression in the regenerating liver was observed by indirect immunofluorescence microscopy, with peak nuclear expression at 30 h post-PH. Rb-related proteins with apparent molecular masses of 300, 156, and 74 kDa were detected in regenerating liver using mAbs to the Rb protein. Their expression increased 6- to 8-fold during regeneration, and only p156 returned to baseline levels at 60 h post-PH. Rb and its related proteins were detected in cultured primary hepatocytes, and although total protein levels did not change appreciably, there was a dramatic shift from cytosol into nuclei through 96 h. The half-life of the Rb protein was determined to be 1.9 h in regenerating liver and 2.2 h in cultured primary hepatocytes. Rb protein abundance in synchronized HuH-7 human hepatoma cells was cell cycle dependent and exhibited peak nuclear expression during S phase. Rb protein was detected primarily in its hyperphosphorylated state during liver regeneration and through the cell cycle of the HuH-7 cells. In vivo administration of transforming growth factor beta 1, an inhibitor of DNA synthesis in regenerating liver, resulted in reduced expression of Rb as well as its protein partners, cell cycle-dependent kinase 4 and cyclin E. The results suggest that in the regenerating rat liver and in synchronized HuH-7 cells, expression of Rb protein is modulated in a cell cycle-dependent fashion, remains primarily in a hyperphosphorylated state, and exhibits a relatively short half-life. The inhibition of Rb protein expression by transforming growth factor beta 1 may be linked to its simultaneous suppression of cell cycle-dependent kinase 4 and cyclin E protein levels.
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PMID:Modulation of retinoblastoma and retinoblastoma-related proteins in regenerating rat liver and primary hepatocytes. 856 85

A protein kinase inhibitor K252a suppressed the growth of HuH7 hepatoma cells and the hyperphosphorylation of retinoblastoma protein (pRb) at late G1 phase of cell cycle. However, K252a treatment did not alter the levels of cyclin D1, cyclin E, cyclin A and Cdk2 protein bound to cyclin E or cyclin A. Therefore, the K252a inhibition of pRb phosphorylation is considered to be brought about probably by inhibiting the action of Cdk-cyclin complex rather than by changing its cellular level. These results also suggest that K252a is a useful tool for investigating the mechanism of phosphorylation of pRb mediated by Cdk-cyclin.
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PMID:K252a inhibits the phosphorylation of pRb without changing the levels of G1 cyclins and Cdk2 protein in human hepatoma cells. 869 9

In the present study, we describe that ginsenoside-Rg1 (G-Rg1) stimulates the proliferation of cultured human hepatoma SK-HEP-1 cells. The incorporation of [3H] thymidine into DNA was increased in the cells in response to G-Rg1. The stimulatory effect of G-Rg1 on DNA synthesis in SK-HEP-1 cells require newly synthesized proteins, since cycloheximide blocked the DNA synthetic activity stimulated with G-Rg1. Thus, we examined whether G-Rg1 induces the intracellular protein levels of regulatory proteins for cell cycle progression using immunoblottings. The results from immunoblottings showed that G-Rg1 induced the levels of cyclin E and cdk2 proteins in the cells. Furthermore, the results from immuno-complex kinase assays for cyclin E-dependent kinase showed that G-Rg1 up-regulates the kinase activity in a dose-dependent manner. These results suggest that G-Rg1 stimulates cell-growth of SK-HEP-1 cells by inducing the intracellular levels of cyclin E/cdk2 complex, which in turn up-regulates cyclin E-dependent kinase activity.
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PMID:Ginsenoside-Rg1 positively regulates cyclin E-dependent kinase activity in human hepatoma SK-HEP-1 cells. 882 5

In the present study, we show that aloesin, which is a low molecular weight ingredients present in Aloe vera, stimulates the proliferation of cultured human hepatoma SK-HEP-1 cells. The incorporation of [3H] thymidine into DNA in the cell cultures was significantly increased at a dose of 10 microM aloesin. The aloesin-induced DNA synthesis appears to require newly synthesized proteins because cycloheximide treatment blocked the DNA synthesis evoked by this compound. We then examined whether this compound increases the intracellular levels of cell cycle regulators by immunoblotting. The data showed that aloesin increased the levels of cyclin E, CDK2, and CDC25A in SK-HEP-1 cells. In addition, immuno-complex kinase assays showed that aloesin up-regulated the enzyme activity of cyclin E/CDK2 kinase in a dose-dependent manner. Collectively, these results suggest that aloesin stimulates the proliferation of SK-HEP-1 cells by inducing the intracellular levels of cyclin E/CDK2 kinase complex and CDC25A, which, together, result in the up-regulation of cyclin E-dependent kinase activity.
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PMID:Aloesin up-regulates cyclin E/CDK2 kinase activity via inducing the protein levels of cyclin E, CDK2, and CDC25A in SK-HEP-1 cells. 906 68

In the present study, we report that ginsenoside-Rg5 (G-Rg5), a newly discovered diol-containing ginsenoside, blocks the cell cycle of human hepatoma SK-HEP-1 cells via the down-regulation of cyclin E-dependent kinase activity. The results from flow cytometric analyses show that G-Rg5 arrests the cell cycle of SK-HEP-1 cells at the Gl/S transition phase. The cyclin E-dependent kinase activity that has been immunoprecipitated with cyclin E-specific antibody is down-regulated in response to G-Rg5. The results from immunoblottings show that the down-regulation of cyclin E-dependent kinase activity is related to increased protein levels of p21Cip/WAF1 and to decreased protein levels of cyclin E, CDK2, and CDC25A. Collectively, these data suggest that G-Rg5 blocks cell cycle of SK-HEP-1 cells at the Gl/S transition phase by down-regulating cyclin E-dependent kinase activity and that the down-regulation of cyclin E-dependent kinase activity is caused mainly by induced CDK2 inhibitor, p21Cip/WAF1 and decreased levels of cyclin E.
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PMID:Ginsenoside-Rg5 suppresses cyclin E-dependent protein kinase activity via up-regulating p21Cip/WAF1 and down-regulating cyclin E in SK-HEP-1 cells. 913 50

Prolinedithiocarbamate (PDTC) and diethyldithiocarbamate (DDTC) are cancer chemopreventive agents and can be biotransformed to prolinethiuramdisulfide (PTDS) and tetraethylthiuramdisulfide (disulfiram; DTDS), respectively. We found that the reactive metabolites PTDS and DTDS induced apoptosis after G1/S arrest. Phosphorylation of cyclin E, inhibition of cyclin-dependent kinase 2 activity, and degradation of cyclin E were found in human hepatoma Hep G2 cells during apoptosis. Moreover, PTDS and DTDS decreased the level of bcl-2 but increased the level of p53. In contrast, PDTC, DDTC, and ammonium dithiocarbamate (ADTC) did not induce apoptosis; rather they led to the induction of p53 and p21 followed by G1/S arrest. PDTC, DDTC, and ADTC also arrested cells in G1 phase. We then examined the effects of PTDS and DTDS on the signal transduction mechanisms leading to apoptosis. Although the transcription factors NFkappaB and AP-1 cooperatively decreased their DNA-binding activities to kappaB and 12-O-tetradecanoylphorbol-13-acetate-responsive elements, respectively, and p53 increased DNA-binding activity in the early stage but decreased it in the latter stage after treatment with PTDS, when the human Hep G2 cells were undergoing apoptosis. In summary, our results indicated that (i) PTDS and DTDS induced apoptosis and G1/S arrest mediated by p53, whereas PDTC, DDTC, and ADTC induced p53-dependent p21 expression leading to G1/S arrest; (ii) PDTC, DDTC, and ADTC induced p21/KIP1/CIP1 expression in a p53-dependent pathway leading to G1/S arrest; and (iii) NFkappaB, AP-1, and bcl-2 were downregulated during PTDS- and DTDS-induced apoptosis. These results suggested that PTDS and DTDS induced p53-dependent apoptosis, whereas PDTC, DDTC, and ADTC induced G1/S arrest. Apoptosis is regulated by the modulation of intracellular effectors such as NFkappaB, AP-1, and bcl-2 and activation of p53 in early stages.
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PMID:Induction of apoptosis by thiuramdisulfides, the reactive metabolites of dithiocarbamates, through coordinative modulation of NFkappaB, c-fos/c-jun, and p53 proteins. 972 16

Classical cytotoxic therapy has been minimally useful in the treatment of hepatocellular carcinoma. In an effort to develop a new approach to the treatment of this neoplasm, we have investigated the signal transduction pathways regulating the growth of human hepatoma cells. In the data reported here, cyclic AMP (cAMP), a negative growth regulator for many cells of epithelial origin, induced G1 synchronization and apoptosis in the HepG2 human hepatoma cell line. The effects of cAMP on the components of the G1/S transition were analyzed. There was no detectable effect of two different cAMP analogs, 8-bromo cAMP or dibutyryl cAMP on the level of the D-type cyclins, cyclin E, cyclin-dependent kinase 2, cyclin-dependent kinase 4, p53, or the cyclin-dependent kinase inhibitors p21 or p27. In contrast, the cAMP analogs induced a dramatic downregulation of cyclin A protein, cyclin A messenger RNA, and cyclin A-dependent kinase activity. Cyclin A-dependent kinase has been shown to be required for the G1-S transition. Furthermore, cyclin A deregulation has been implicated in the pathogenesis of hepatocellular carcinoma. The data reported here suggest a novel signal transduction-based approach to hepatoma therapy.
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PMID:Cyclic AMP induces inhibition of cyclin A expression and growth arrest in human hepatoma cells. 1020 5

The peroxisome proliferators are rodent non-genotoxic hepatocarcinogens that suppress apoptosis and induce DNA replication, cell proliferation and liver tumours. In order to investigate the effect of peroxisome proliferators on cell cycle progression, we arrested the well-differentiated rat hepatoma cell line FaO in the G1 phase of the cell cycle. Under these conditions, CDK2 and CDK4 protein expression remained unchanged compared with proliferating cells, but expression of cyclin D1 and p27(KIP1) was down-regulated and cyclin E accumulated in the inactive form. G1-arrested cells were able to enter the cell cycle on addition of exogenous growth factors such as epidermal growth factor (EGF) or hepatocyte growth factor (HGF) and replicate their DNA within 12 to 24 h of re-stimulation. Upon release from G1 arrest, CDK2 protein expression was down-regulated and, surprisingly, p27(KIP1) expression was restored. Cyclin D1 and phosphorylated cyclin E accumulated at 12 h but were degraded by 24 h after addition of EGF. Importantly, the peroxisome proliferator nafenopin and tumour necrosis factor alpha were able to induce DNA replication. Thus, the profile of expression of cell cycle regulatory proteins upon stimulation with nafenopin is comparable with that induced by growth factors such as EGF.
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PMID:G1-arrested FaO cells re-enter the cell cycle upon stimulation with the rodent non-genotoxic hepatocarcinogen nafenopin. 1038 91

In the Solt-Faber model DENA and 2-Acetaminofluorene (AAF) treatment combined with hepatectomy induces hepatocellular carcinoma in rats. In this model AAF blocks proliferation of hepatocytes, while oval cells restore liver mass. Here we studied the molecular mechanism involved in blocking AAF-dependent cell cycle progression of hepatocytes. AAF inhibits cell proliferation of hepatocytes shown by the lack of Cyclin E expression before the G1/S phase restriction point. Immunfluorescence studies revealed that Cyclin E positive signals were restricted to oval cells, while hepatocytes remained negative. Additionally, AAF treatment induces strong nuclear p53 expression which is associated with increased p21 mRNA levels. Inhibition of active Cyclin/CdK (cyclin dependent kinase) complexes is reflected in AAF-treated animals by decreased RB expression and phosphorylation. The decrease in RB expression and phosphorylation, which is essential in triggering DNA synthesis and Cyclin A expression, leads to a deficiency in transcriptionally active E2F complex formation after hepatectomy. Thus, two molecular explanations are evident to account for AAF-dependent cell cycle progression of hepatocytes in vivo: first, induction of p53 expression which leads to higher p21 mRNA levels, and second, a lack of Cyclin E expression at the G1/S phase restriction point after hepatectomy.
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PMID:2-acetaminofluorene blocks cell cycle progression after hepatectomy by p21 induction and lack of cyclin E expression. 1059 46

Transforming growth factor beta (TGF-beta)-mediated G(1) arrest previously has been shown to specifically target inactivation of cyclin D:cyclin-dependent kinase (Cdk) 4/6 complexes. We report here that TGF-beta-treated human HepG2 hepatocellular carcinoma cells arrest in G(1), but retain continued cyclin D:Cdk4/6 activity and active, hypophosphorylated retinoblastoma tumor suppressor protein. Consistent with this observation, TGF-beta-treated cells failed to induce p15(INK4b), down-regulate CDC25A, or increase levels of p21(CIP1), p27(KIP1), and p57(KIP2). However, TGF-beta treatment resulted in the specific inactivation of cyclin E:Cdk2 complexes caused by absence of the activating Thr(160) phosphorylation on Cdk2. Whole-cell lysates from TGF-beta-treated cells showed inhibition of Cdk2 Thr(160) Cdk activating kinase (CAK) activity; however, cyclin H:Cdk7 activity, a previously assumed mammalian CAK, was not altered. Saccharomyces cerevisiae contains a genetically and biochemically proven CAK gene, CAK1, that encodes a monomeric 44-kDa Cak1p protein unrelated to Cdk7. Anti-Cak1p antibodies cross-reacted with a 45-kDa human protein with CAK activity that was specifically down-regulated in response to TGF-beta treatment. Taken together, these observations demonstrate that TGF-beta signaling mediates a G(1) arrest in HepG2 cells by targeting Cdk2 CAK and suggests the presence of at least two mammalian CAKs: one specific for Cdk2 and one for Cdk4/6.
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PMID:Transforming growth factor beta targeted inactivation of cyclin E:cyclin-dependent kinase 2 (Cdk2) complexes by inhibition of Cdk2 activating kinase activity. 1061 20


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