The expression of oncogenes in human developing liver and hepatomas

Zhang, Xiaokun; Huang, Dao-Pei; Chiu, De-Kai; Chiu, Jen‐Fu

doi:10.1016/0006-291x(87)91503-8

Cited by 54 publications

(21 citation statements)

References 26 publications

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“…Of ten compounds tested, two were highly effective suppressors, namely, 2-AP and staurosporine. The mechanism of 2-AP inhibition of cellular phosphorylation is not well understood, but it is believed to block protein kinases by modifying serine and threonine residues (71,74). Whether 2-AP acts as a general or a specific protein kinase inhibitor seems to depend largely on the experimental system under study (24,76), although 2-AP shows a certain preference for the heme-regulated eukaryotic initiation factor eIF-2 kinase (13,24).…”

Section: Discussionmentioning

confidence: 99%

“…As a control for these experiments, we used the c-myc gene, whose transcriptional status in hepatoma cells is very different from that found in other cultured cell lines. Steady-state C-MYC mRNA levels are high in untreated hepatoma cells (18,38,58,67,74,75) and, after an initial rise, do not change during prolonged exposure to TPA (18). We found that prolonged TPA treatment, however, has a dramatic effect on TCDD inducibility of the Cypla-l gene (Fig.…”

Section: Controls Include Cip-untreated Extracts From Cells Not Treatmentioning

confidence: 99%

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Dioxin-dependent activation of murine Cyp1a-1 gene transcription requires protein kinase C-dependent phosphorylation.

Carrier¹,

Owens²,

Nebert³

et al. 1992

Mol. Cell. Biol.

146

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Transcriptional activation of the murine Cypla-l (cytochrome P1450) gene by inducers such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (dioxin) requires the aromatic hydrocarbon (Ah) receptor and the interaction of an inducer-receptor complex with one or more of the Ah-responsive elements (AhREs) located about 1 kb upstream from the transcriptional initiation site. We find that treatment of mouse hepatoma Hepa-1 cells with 2-aminopurine, an inhibitor of protein kinase activity, inhibits CYPlAl mRNA induction by TCDD as well as the concomitant increase in CYPlAl enzyme activity. Formation of DNA-protein complexes between the Ah receptor and its AhRE target is also inhibited by 2-aminopurine, as determined by gel mobility shift assays. Phosphorylation is required for the formation of Ah receptor-specific complexes, since in vitro dephosphorylation of nuclear extracts from TCDD-treated Hepa-1 cells abolishes the capacity of the Ah receptor to form specific complexes with its cognate AhRE sequences. To determine whether any one of several known protein kinases was involved in the transcriptional regulation of the Cypla-1 gene, we treated Hepa-1 cells with nine other protein kinase inhibitors prior to induction with TCDD; nuclear extracts from these cells were analyzed for their capacity to form specific DNA-protein complexes. Only extracts from cells treated with staurosporine, a protein kinase C inhibitor, were unable to form these complexes. In addition, staurosporine completely inhibited CYPlAl mRNA induction by TCDD. Depletion of protein kinase C by prolonged treatment with phorbol ester led to the complete suppression of CYPlAl mRNA induction by TCDD. We conclude that (i) phosphorylation is necessary for the formation of a transcriptional complex and for transcriptional activation of the Cypla-) gene; (ii) the phosphorylation site(s) exists on at least one of the proteins constituting the transcriptional complex, possibly the Ah receptor itself; and (iii) the enzyme responsible for the phosphorylation is likely to be protein kinase C.The mammalian CYPJAl gene encodes an enzyme expressed endogenously during cell division, embryogenesis, and differentiation, suggesting that this gene as well as certain other P450 genes might be involved in distinct critical life processes (51,53). The CYPlAl enzyme also plays an important role in the detoxification of numerous polycyclic aromatic hydrocarbons, including benzo[a]pyrene, a major component in the production of cigarette smoke and other combustion processes. Moreover, CYPlAl is an essential enzyme in the detoxification of chemicals responsible for activation of the CYPIAI gene, and paradoxically, the enzyme also potentiates promutagens and procarcinogens by converting them into reactive intermediates (cf. references 53 and 60 and references therein from the transcriptional initiation site (14,19,26,28,40,55,56). As a consequence of gene activation, the rates of CYPlAl mRNA and protein synthesis are increased 20-to 100-fold (for a review, see reference 54). Posttrans...

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Section: Discussionmentioning

confidence: 99%

Section: Controls Include Cip-untreated Extracts From Cells Not Treatmentioning

confidence: 99%

Dioxin-dependent activation of murine Cyp1a-1 gene transcription requires protein kinase C-dependent phosphorylation.

Carrier¹,

Owens²,

Nebert³

et al. 1992

Mol. Cell. Biol.

146

View full text Add to dashboard Cite

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“…However, no completely satisfactory predictive factors have been identi®ed. Furthermore, no genetic markers for recurrence of HCC been delineated either (Himeno et al, 1988;Zhang et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

Correlation of postoperative recurrence in hepatocellular carcinoma with demethylation of repetitive sequences

Itano

Ueda

Kikuchi³

et al. 2002

Oncogene

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Restriction landmark genomic scanning (RLGS) was utilized to identify novel genomic alterations in hepatocellular carcinoma (HCC). Thirty-one HCC samples were examined by RLGS. Two high intensity spots were common to several RLGS pro®les of di erent HCCs. Nucleotide sequencing and homology search analysis showed that these spots represented repetitive sequences, Human tandem repeat sequence (Genbank, L09552) and centromeric NotI cluster (Genbank, Y10752). These intensi®ed signals were attributable to the occurrence of demethylated areas in the recognition sequence of the NotI site of the corresponding fragments. The intensity of these spots in the RLGS pro®le re¯ects their degree of demethylation, which was signi®cantly correlated with postoperative recurrence, even in patients regarded as belonging to the good prognosis group by conventional prognostic factors. Multivariate analysis showed that the intensities of the two spots retained independent prognostic value. This is a new type of predictive factor for HCC based on epigenetic changes in hepatocarcinogenesis, and in the future it is expected to be of great value in making preoperative diagnosis and selecting postoperative therapy.

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“…This independence from growth factor requirements raises the question of whether products of activated cellular oncogenes (c-oncs) are involved in the process of liver carcinogenesis [4][5][6][7] and activation of c-oncs in HCC tissues has recently been demonstrated [8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Expression of high‐ and low‐affinity epidermal growth factor receptors in human hepatoma cell lines

Clementi¹,

Festa

Testa

et al. 1989

FEBS Letters

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Data are presented from a comparative research on expression of epidermal growth factor (EGF) receptors and response to EGF of six independently established cell lines derived from human hepatoma. These lines differ in terms of the degree of differentiation, presence of hepatitis B virus (HBV) DNA copies in integrated form and expression of HBV genes. Our results indicate differential expression of membrane EGF receptors and differential response to EGF under serumand hormone-free culture conditions. Furthermore, a significant difference in affinity could be detected between EGF receptors of the two highly dedifferentiated cell lines (HA22T/VGH and Li7A) whose replication is inhibited by EGF concentrations capable of stimulating more differentiated phenotypes.Epidermal growth factor receptor; Cell replication; (Human hepatoma cell)

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The expression of oncogenes in human developing liver and hepatomas

Cited by 54 publications

References 26 publications

Dioxin-dependent activation of murine Cyp1a-1 gene transcription requires protein kinase C-dependent phosphorylation.

Dioxin-dependent activation of murine Cyp1a-1 gene transcription requires protein kinase C-dependent phosphorylation.

Correlation of postoperative recurrence in hepatocellular carcinoma with demethylation of repetitive sequences

Expression of high‐ and low‐affinity epidermal growth factor receptors in human hepatoma cell lines

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