UMLS:C0019204 - FACTA Search

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A monocyte chemotactic activity was found to be released by various types of cultured human cells after appropriate stimulation: normal diploid fibroblasts, peripheral blood mononuclear cells or monocytes isolated therefrom, and a number of tumor cell lines, including osteosarcoma (MG-63) and hepatoma (Malavu) but not melanoma (Bowes) cells. Cultures of diploid human fibroblasts and these tumor cells stimulated with interleukin (IL) 1 or double-stranded RNA [poly(rI).poly(rC)], or infected with viruses (measles or rubella viruses) were found to produce chemotactic activity for both monocytes and granulocytes. Media collected from fibroblasts treated with E. coli or IL 6 did not contain such activity. Granulocyte and monocyte chemotactic activities were serologically distinct, and could be separated by successive chromatographical procedures. While the granulocyte chemotactic activity of both fibroblasts and MG-63 cells had previously been identified as granulocyte chemotactic protein/IL 8, the monocyte chemotactic activity from MG-63 cells was identified by amino acid sequence analysis as a different protein recently described to be released by human glioma and myelomonocytic cell lines. In view of the similarity in their chromatographical behavior, monocyte chemotactic activities from fibroblasts, MG-63 cells and fresh monocytes can probably be assigned to identical molecules. Cultures of unfractionated peripheral blood cells, however, were found to release an additional monocyte chemotactic protein, identifiable by amino acid sequence analysis as platelet factor 4.
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PMID:Identification by sequence analysis of chemotactic factors for monocytes produced by normal and transformed cells stimulated with virus, double-stranded RNA or cytokine. 269 Dec 59

Structural changes of the human retinoblastoma gene have been demonstrated previously in retinoblastoma and some clinically related tumors including osteosarcoma. Structural aberrations of the retinoblastoma locus (RB1) were observed in 25% of breast tumor cell lines studied and 7% of the primary tumors. These changes include homozygous internal deletions and total deletion of RB1; a duplication of an exon was observed in one of the cell lines. In all cases, structural changes either resulted in the absence or truncation of the RB1 transcript. No obvious defect in RB1 was detected by DNA blot analysis in primary tumors or cell lines from Wilms' tumor, cervical carcinoma, or hepatoma. These results further support the concept that the human RB1 gene has pleiotropic effects on specific types of cancer.
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PMID:Structural rearrangement of the retinoblastoma gene in human breast carcinoma. 317 51

Recently, Kalvakolanu et al. (Kalvakolanu, D. V. R., Liu, J., Hanson, R. W., Harter, M. L., and Sen, G. C. (1992) J. Biol. Chem. 267, 2530-2536) showed that E1A inhibited the basal and cAMP-stimulated transcription of the gene for phosphoenolpyruvate carboxykinase (PEPCK). This inhibition was mediated by the conserved region 1 (CR1) domain of E1A, which has been shown by other laboratories to bind to the cellular transcriptional adaptor proteins, p300 and cAMP response element binding protein (CREB)-binding protein (CBP). The PEPCK gene promoter contains a functional cAMP-response element, through which CREB and, therefore, CBP modulate transcription, and a consensus p300 DNA binding sequence is also present in a distal protein binding site of the promoter. We hypothesized that E1A might inhibit PEPCK gene transcription by binding to p300 and/or CBP. Surprisingly, we found that E1A consistently stimulated basal transcription from the PEPCK promoter in transfection assays in adenovirus (Ad)-infected HepG2 hepatoma cells or E1A-expressing, stably transfected 3T3 fibroblasts and nuclear run-on assays in Ad-infected H4IIE hepatoma cells. E1A also enhanced the stimulation of PEPCK gene transcription by Bt2cAMP. In transfection assays, wild type Ad5 expressing both 243R and 289R forms of E1A or a mutant virus expressing the 289R form alone stimulated transcription from the PEPCK promoter by approximately 5-fold 20 h postinfection. However, no stimulation was observed in cells infected with a virus expressing either the 243R protein alone or a 289R protein from which conserved region 3 (CR3) was mutated. Mutation or deletion of CR1 of E1A had no significant effect on transcription from the PEPCK promoter. Mutations within conserved region 2 (CR2) of E1A that inhibit the binding of E1A to the retinoblastoma gene product (pRb) further enhanced the stimulation of transcription from the PEPCK promoter by 2 3-fold compared with wild type E1A. These findings suggested that the normal function of pRb is to stimulate PEPCK gene transcription, and that this process is inhibited by the binding of E1A to pRb. This hypothesis was confirmed by overexpressing pRb in HepG2 cells, which stimulated transcription from the PEPCK promoter. Our findings indicate that Ad E1A regulates PEPCK gene transcription through a stimulatory mechanism involving CR3, and by attenuating a stimulatory effect of pRb through CR2.
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PMID:Adenovirus E1A proteins regulate phosphoenolpyruvate carboxykinase gene transcription through multiple mechanisms. 862 93

Transforming growth factor-beta1 (TGF-beta1) can induce rapid growth arrest and apoptosis in hepatic cells. Its growth suppressive effects appear to be linked to decreased phosphorylation of the protein product of the retinoblastoma gene, pRb. To characterize the role of pRb in apoptosis, we examined endogenous retinoblastoma gene (Rb) expression following treatment with TGF-beta1, okadaic acid, or antisense Rb S-oligonucleotides in cultured primary rat hepatocytes and human hepatoma HuH-7 cells. We also investigated the effects on apoptosis of Rb overexpression following transfection with vectors containing wild-type Rb in HuH-7 cells. Our results indicated that transfection with Rb antisense S-oligonucleotides blocked the expression of pRb in cultured primary hepatocytes and induced apoptosis. Treatment of HuH-7 cells with TGF-beta1 inhibited expression and phosphorylation of pRb, and also induced apoptosis. Furthermore, 93% of viable preapoptotic cells were arrested in the G1 phase of the cell cycle. Incubation with the phosphatase inhibitor okadaic acid maintained pRb in its phosphorylated state, and resulted in significant apoptosis. Overexpression of wild-type Rb inhibited TGF-beta1 induced apoptosis in HuH-7 cells. In contrast, overexpression of transcription factor E2F-1, a known target for the activity of pRb, caused significant apoptosis. However, coexpression of Rb suppressed E2F-1 induced apoptosis in HuH-7 cells. Our results suggest that inhibition of pRb expression is associated with hepatocyte apoptosis. Furthermore, E2F-1 appears to be a target in the pathway through which pRb modulates the apoptotic threshold in hepatic cells. Finally, the data suggest that these cells exit the cell cycle during the G1 phase before progressing into apoptosis and pRb may be a negative regulator of this process.
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PMID:The retinoblastoma gene product inhibits TGF-beta1 induced apoptosis in primary rat hepatocytes and human HuH-7 hepatoma cells. 864 52

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 cycling cells, the retinoblastoma protein (pRb) is un- and/or hypo-phosphorylated in early G1 and becomes hyper-phosphorylated in late G1. The role of hypo-phosphorylation and identity of the relevant kinase(s) remains unknown. We show here that hypo-phosphorylated pRb associates with E2F in vivo and is therefore active. Increasing the intracellular concentration of the Cdk4/6 specific inhibitor p15(INK4b) by transforming growth factor beta treatment of keratinocytes results in G1 arrest and loss of hypo-phosphorylated pRb with an increase in unphosphorylated pRb. Conversely, p15(INK4b)-independent transforming growth factor beta-mediated G1 arrest of hepatocellular carcinoma cells results in loss of Cdk2 kinase activity with continued Cdk6 kinase activity and pRb remains only hypo-phosphorylated. Introduction of the Cdk4/6 inhibitor p16(INK4a) protein into cells by fusion to a protein transduction domain also prevents pRb hypo-phosphorylation with an increase in unphosphorylated pRb. We conclude that cyclin D:Cdk4/6 complexes hypo-phosphorylate pRb in early G1 allowing continued E2F binding.
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PMID:Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexes results in active pRb. 938 Jun 98

The oncogene c-myc and transforming growth factor (TGF) alpha are frequently coexpressed in human cancers, suggesting that their interaction may be a critical step in malignant growth. Consistent with this idea, we recently demonstrated in a transgenic mouse model that TGF-alpha dramatically enhances c-myc-induced hepatocarcinogenesis. To elucidate this synergistic effect, we have now investigated regulation of cell cycle and apoptosis during neoplastic development in the liver of c-myc and c-myc/TGFalpha transgenic mice. Both lines displayed dramatic increases of mitotic and apoptotic rates before the onset of hepatocellular carcinoma (HCC), but only c-myc/TGF-alpha livers showed significant levels of net proliferation (mitosis minus apoptosis). Subsequently, mitosis declined in peritumorous tissues, concomitant with the previously reported induction of TGF-beta1, whereas c-myc and c-myc/TGFalpha HCCs maintained mitotic hyperactivity. The c-myc/TGF-alpha HCCs were also characterized by a particularly strong expression of TGF-alpha and very low apoptotic index in contrast to high levels of apoptosis in peritumorous tissues and c-myc HCCs. The differential levels of cell proliferation in noncancerous and cancerous tissues correlated with a stronger induction of cyclin D1 mRNA and protein in c-myc/TGF-alpha and c-myc HCCs associated with intense pRb hyperphosphorylation. Severe deregulation of G1-S transition was also indicated by the dramatic up-regulation, particularly in the HCCs, of pRb-free E2F1-DP1 and E2F2-DP1 transcription factor heterodimers, as assessed by immunoprecipitation and immunohistochemistry. The existence of increased E2F activity during hepatocarcinogenesis was further indicated by the transcriptional induction of putative E2F target genes involved in cell cycle progression, such as endogenous c-myc, cyclin A, Cdc2, and E2F itself. Cdc2 overexpression and the elevated mitotic indices in the HCCs correlated also with induction of cyclin B steady-state levels. The data suggest that coexpression of c-myc and TGF-alpha leads to a selective growth advantage for hepatic (pre)neoplastic cells by disrupting the pRb/E2F pathway and by TGF-alpha-mediated reduction of apoptosis.
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PMID:Disruption of the pRb/E2F pathway and inhibition of apoptosis are major oncogenic events in liver constitutively expressing c-myc and transforming growth factor alpha. 942 68

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor in eukaryotic cells that alters gene expression in response to the environmental contaminant 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD). In 5L hepatoma cells, TCDD induces a G1 cell cycle arrest through a mechanism that involves the AhR. The retinoblastoma tumor suppressor protein (pRb) controls cell cycle progression through G1 in addition to promoting differentiation. We examined whether the human AhR or its dimerization partner, the AhR nuclear translocator, interacts with pRb as a basis of the TCDD-induced cell cycle arrest. In vivo and in vitro assays reveal a direct interaction between pRb and the AhR but not the AhR nuclear translocator protein. Binding between the AhR and pRb occurs through two distinct regions in the AhR. A high affinity site lies within the N-terminal 364 amino acids of the AhR, whereas a lower affinity binding region colocalizes with the glutamine-rich transactivation domain of the receptor. AhR ligand binding is not required for the pRb interaction per se, although immunoprecipitation experiments in 5L cells reveal that pRb associates preferentially with the liganded AhR, consistent with a requirement for ligand-induced nuclear translocation. These observations provide a mechanistic insight into AhR-mediated cell cycle arrest and a new perspective on TCDD-induced toxicity.
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PMID:A direct interaction between the aryl hydrocarbon receptor and retinoblastoma protein. Linking dioxin signaling to the cell cycle. 971 1

G1 phase progression of mammalian cells is mainly controlled by the cyclin-cyclin-dependent kinase (CDK)-CDK inhibitor-retinoblastoma protein (pRb) regulatory pathway. Cell cycle regulators controlling G1 phase progression are frequently involved in the carcinogenesis of many human cancer types. In hepatocellular carcinoma (HCC) the CDK inhibitor p16INK4 is predominantly inactivated by post-transcriptional regulation and p16INK4 inactivation participates in the early-stage of hepatocarcinogenesis and in disease progression. Reduced p21(WAF1/CIP1) expression, which is associated mainly with p53 gene mutation in HCCs, contributes to hepatocarcinogenesis. Reduced p27Kip1 expression is also frequently involved in HCC. The CDK inhibitors p16INK4, p21(WAF1/CIP1) and p27Kip1 are independently affected and a change in the expression of one or more of these inhibitors contributes to carcinogenesis of the majority (nearly 90%) of HCCs. Cyclin D1 amplification and overexpression play a role in the carcinogenesis of a subset (11-13%) of HCCs. Disruption of the regulatory system controlling G1 phase progression is a common event in human hepatocarcinogenesis. Further studies systematically analyzing the major regulators controlling G1 phase progression in a large cohort of HCCs will strengthen our understanding of the molecular mechanism underlying human hepatocarcinogenesis. Correcting alterations that have occurred in the G1 phase regulatory machinery may provide a novel weapon to treat and prevent HCC.
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PMID:Cell cycle regulators and human hepatocarcinogenesis. 984 Jan 20

Ceramide is known to induce pRb (retinoblastoma gene product) dephosphorylation through the activation of ceramide-activated protein phosphatase (CAPP) during G1 arrest, but other molecular mechanisms linked to regulation of pRb dephosphorylation during ceramide-induced G1 arrest are poorly understood. In this paper, we investigated whether p21, a cdk (cyclin-dependent kinase) inhibitor, is involved in the induction of pRb dephosphorylation during ceramide-induced G1 arrest. In SK-Hep-1 cells, the addition of ceramide resulted in pRb dephosphorylation and G1 arrest. The activity of cdk2 was inhibited in response to ceramide during this process. p21 protein and mRNA were remarkably induced, while the protein level of p53, known as a transcriptional activator of p21, was not elevated at the same condition. p21 induction was also observed in the Hep3B cells lacking a functional p53 after exposure to ceramide. Although p21 is induced in ceramide-treated Hep3B cells, Hep3B cells do not induce G1 arrest, because Hep3B cells are deficient in a functional pRb protein. To confirm that pRb is a critical target for the induction of G1 arrest by inhibiting cdk2 activity through p53-independent p21, pRb-expressing vector was transfected into Hep3B cells. After treatment with ceramide, pRb-expressing cells (pRb+/+), but not pRb-/- cells, were arrested in G1 phase. In pRb+/+ cells, ceramide-mediated G1 arrest was accompanied by the accumulation of hypophosphorylated pRb and p21 associated with cdk2. Together, these results suggest that p21, induced through p53-independent pathway, participates in the induction of pRb dephosphorylation by inhibiting cdk2 activity during ceramide-mediated G1 arrest in hepatocarcinoma cells.
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PMID:Induction of p53-independent p21 during ceramide-induced G1 arrest in human hepatocarcinoma cells. 1087 74

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