Cytoplasmic retention of the p53 tumor suppressor gene product is observed in the hepatitis B virus X gene-transfected cells

Takada, Shinako; Kaneniwa, Noriko; Tsuchida, Nobuo; Koike, Katsuro

doi:10.1038/sj.onc.1201369

Cited by 81 publications

(69 citation statements)

References 31 publications

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“…The adenovirus E1B 55-kDa protein binds to p53 and prevents the nuclear localization of p53 (Zantema et al, 1985a,b). p53 exclusion from the nucleus has also been described in hepatitis B virus X gene-expressing cells (Ueda et al, 1995;Elmore et al, 1997;Takada et al, 1997). Our results suggest that the HCV NS5A binds to and colocalizes p53 in perinucleoplasmic region of cytoplasm.…”

Section: Discussionsupporting

confidence: 71%

HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis

Sheu²,

et al. 2002

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Hepatitis C virus (HCV) causes a persistent infection, chronic hepatitis and hepatocellular carcinoma. HCV NS5A, one of non-structural proteins of HCV, was suggested to play a role in oncogenic transformation. Since the tumor suppressor p53 is important for preventing neoplastic transformation, we investigated the functional effects of HCV NS5A on p53. In vitro and in vivo coimmunoprecipitation and confocal microscopy were used to determine the interaction of NS5A and p53. HCV NS5A binds directly to p53 and colocalizes p53 in the perinuclear region. NS5A inhibits transcriptional transactivation by p53 in a dose-dependent manner by use of a reporter assay. Down regulation of endogenous p21/waf1 expression, which is activated by p53 in Hep3B cells, by NS5A was demonstrated by using FLAG-and FLAG-NS5A Hep3B stable cell lines. The effect of NS5A on p53-mediated apoptosis was determined by flow cytometry in both NS5A permanently and transiently transfected Hep3B cells with exogenous p53. The p53-induced apoptosis was abrogated by NS5A and the inhibition effect correlates well with the binding ability of NS5A to p53. In addition, HCV NS5A protein interacts with and colocalizes hTAF II 32, a component of TFIID and an essential coactivator of p53, in vivo. These results suggest that HCV NS5A interacts with and partially sequestrates p53 and hTAF II 32 in the cytoplasm and suppresses p53-mediated transcriptional transactivation and apoptosis during HCV infection, which may contribute to the hepatocarcinogenesis of HCV infection.

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Section: Discussionsupporting

confidence: 71%

HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis

Sheu²,

et al. 2002

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“…HBV-X stimulates cell cycle progression, shortening the emergence of cells from quiescence (G0) and entry into S phase and accelerating transit through checkpoint controls at G0/G1 and G2/M thus participate in the selection of cells that are genetically unstable, some of which would accumulate unrepaired transforming mutations (Benn and Schneider, 1995). Modulation of the apoptosis by the interactions of HBV-X protein and p53 gene product has also been reported (Elmore et al, 1997;Takada et al, 1997;Wang et al, 1994). Anti-apoptotic actions of HBV-X protein as a potent caspase 3 inhibitor has been described (Gottlob et al, 1998).…”

Section: Discussionmentioning

confidence: 95%

Hepatitis B virus-X protein upregulates the expression of p21wafl/cipl and prolongs G1→S transition via a p53-independent pathway in human hepatoma cells

Park

Lee

et al. 2000

Oncogene

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Progression through the cell cycle is controlled by the induction of cyclins and activation of cognate cyclindependent kinases. The human hepatitis B virus-X (HBV-X) protein functions in gene expression alterations, in the sensitization of cells to apoptotic killing and deregulates cell growth arrest in certain cancer cell types. We have pursued the mechanism of growth arrest in Hep3B cells, a p53-mutant human hepatocellular carcinoma (HCC) cell line. In stable or transient HBV-X transformed Hep3B cells, HBV-X increased protein and mRNA levels of the cyclin-dependent kinase inhibitor (CDKI) p21 wa¯/cipl , increased binding of p21 wa¯/cipl with cyclin-dependent kinase 2 (CDK2), markedly inhibited cyclin E and CDK2 associated phosphorylation of histone H1 and induced the activation of a p21 promoter reporter construct. By using p21 promoter deletion constructs, the HBV-X responsive element was mapped to a region between 71185 and 71482, relative to the transcription start site. Promoter mutation analysis indicated that the HBV-X responsive site coincides with the ets factor binding sites. These data indicate that in human hepatocellular carcinoma cells, HBV-X can circumvent the loss of p53 functions and induces critical downstream regulatory events leading to transcriptional activation of p21 wa¯/cipl . As a consequence, there is an increased chance of acquisition of mutations which can enhance the genesis of hepatomas. Our results also emphasize the chemotherapeutic potential of p21 wa¯/cipl inhibitors, particularly in the HBV-X infected hepatoma which lacks functional p53. Oncogene (2000) 19, 3384 ± 3394.

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“…The anti-apoptotic action of HBx via its interaction with the p53 molecule has been demonstrated in cultured human cells (Wang et al, 1995;Su and Schneider, 1997;Takada et al, 1997;Yun et al, 2000). Repression of apoptosis through the inhibition of caspase-3 activity or through the activation of PI3K by HBx in hepatocytes has been reported (Gottlob et al 1998;Shih et al, 2000;Lee et al, 2001).…”

Section: Introductionmentioning

confidence: 97%

Activation of calcium signaling by hepatitis B virus-X protein in liver cells

Jeong²,

Kim³

et al. 2003

Exp Mol Med

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Abbreviations: CREB, cyclic AMP response element binding protein; DMSO, dimethylsulfoxide; ECL, enhanced chemiluminescence. EDTA, ethylenediaminetetraacetic acid; EGTA, ethylene-bis (oxyethylenenitrilo)tetraacetic acid; HCC, hepatocellular carcinoma; IP3, inositol-3-phosphate; MAPK (Erk), mitogen activated protein kinase; NF-AT, nuclear factor of activated T cells; PCNA, proliferative cell nuclear antigen; PI3K, phosphatidylinositol-3-kinase; PIP3, phosphatidylinositol-3-phosphate; SAPK/JNK, stress activated protein kinase/c-Jun N-terminal kinase

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Cytoplasmic retention of the p53 tumor suppressor gene product is observed in the hepatitis B virus X gene-transfected cells

Cited by 81 publications

References 31 publications

HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis

HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis

Hepatitis B virus-X protein upregulates the expression of p21wafl/cipl and prolongs G1→S transition via a p53-independent pathway in human hepatoma cells

Activation of calcium signaling by hepatitis B virus-X protein in liver cells

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