Functional inactivation but not structural mutation of p53 causes liver cancer

Abstract

Structural mutations in the p53 gene are seen in virtually every form of human cancer. To determine whether such mutations are important for initiating tumorigenesis, we have been studying hepatocellular carcinoma, in which most cases are associated with chronic hepatitis B virus infections. Using a transgenic mouse model where expression of a single HBV gene product, the HBx protein, induces progressive changes in the liver, we show that tumour development correlates precisely with p53 binding to HBx in the cytoplasm and complete blockage of p53 entry into the nucleus. Analysis of tumour cell DNA shows no evidence for p53 mutation, except in advanced tumours where a small proportion of cells may have acquired specific base substitutions. Our results suggest that genetic changes in p53 are late events which may contribute to tumour progression.

p53 regulation by post-translational modification and nuclear retention in response to diverse stresses

“…One such mechanism involves aberrant subcellular localization. Constitutive cytoplasmic localization of wildtype p53 has been reported in in¯ammatory breast carcinoma (Moll et al, 1992), colorectal adenocarninoma (Bosari et al, 1995;Sun et al, 1992), undi erentiated neuroblastoma , hepatocellular carcinoma (Ueda et al, 1995), and retinoblastoma (Schlamp et al, 1997), and is associated with tumor metastasis and poor long-term patient survival (Stenmark-Askmalm et al, 1994;Sun et al, 1992). In addition, some viruses induce uncontrolled cell proliferation through a strategy involving p53 cytoplasmic sequestration.…”

“…For example, the adenovirus E1B-55-kDa protein anchors p53 in cytoplasmic structures, reducing p53 transcriptional activity (Blair Zajdel and Blair, 1988;Konig et al, 1999;Sarnow et al, 1982;Yew and Berk, 1992;Zantema et al, 1985). The hepatitis B virus HBx protein localizes p53 to the cytoplasm and inhibits both its transcriptional activity and its ability to mediate apoptosis (Elmore et al, 1997;Feitelson et al, 1993;Ueda et al, 1995;Wang et al, 1994Wang et al, , 1995. Hepatocellular carcinoma is among the most common malignancies world wide, with over 80% of patients positive for Hepatitis B virus infection.…”

p53-independent apoptotic effects of the hepatitis B virus HBx protein in vivo and in vitro

“…Because previous reports had described physical interactions between HBx and p53 proteins that could a ect apoptotic processes (Ueda et al, 1995;Wang et al, 1995), we evaluated the e ect of the p53-null genotype on liver cell apoptosis in HBx-expressing animals. Hybrid mice (HBx/p53 +/7 and HBx/p53 7/7 ) were generated by crossing PEX7 and AX16 transgenics with p53-null mice (Jacks et al, 1994).…”

“…Relevant to how HBx might participate in cell transformation, the X gene product stimulates cell cycle progression, DNA synthesis and apoptosis (Benn and Schneider, 1995;Chirillo et al, 1997;Su and Schneider, 1997). There is also evidence to indicate that HBx may bind a variety of cellular target genes (Fischer et al, 1995;Lee et al, 1995;Sirma et al, 1998), and notably the tumor suppressor protein p53 (Feitelson et al, 1993;Lin et al, 1997;Ueda et al, 1995). HBx was shown to sequester the p53 protein in the cytoplasm and to inactivate its transactivating and apoptotic properties (Elmore et al, 1997;Takada et al, 1997;Truant et al, 1995;Wang et al, 1994Wang et al, , 1995.…”

Disruption of transforming growth factor-β signaling through β-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation

“…Risk factors for HCC include viral hepatitis B and viral hepatitis C (HCV) infection that activate JAK/ STAT signaling, induce overexpression of insulinlike growth factor-II in 16-40% of HCCs (Breuhahn et al, 2006), and disrupt p53, p55 sen and p21 WAF1/CIP1/SDI1 (Ueda et al, 1995;Feitelson, 1999;Huo et al, 2001). Activation of the Wnt signaling pathway with b-catenin mutations is observed in 17-40% of HCCs and axin-2 inactivation in 3-10% of cases (Taniguchi et al, 2002;Ishizaki et al, 2004).…”