The Hepatitis B Virus-X Protein Activates a Phosphatidylinositol 3-Kinase-dependent Survival Signaling Cascade

Abstract

Phosphorylation of Akt at serine 473 and Bad at serine 136 were induced by HBx, which were specifically blocked by wortmannin and dominant negative mutants of Akt and Bad, respectively. We also demonstrated that HBx inhibits caspase 3 activity and HBx down-regulation of caspase 3 activity was blocked by the PI3K inhibitor. Regions required for PI3K phosphorylation on the HBx protein overlap with the known transactivation domains. HBx blocks apoptosis induced by serum withdrawal in CHL cells in a p53-independent manner. The results indicate that, unlike other DNA tumor viruses that block apoptosis by inactivating p53, the hepatitis B virus achieves protection from apoptotic death through a HBx-PI3K-Akt-Bad pathway and by inactivating caspase 3 activity that is at least partially p53-independent in liver cells. Moreover, these data suggest that modulation of the PI3K activity may represent a potential therapeutic strategy to counteract the occurrence of apoptosis in human hepatocellular carcinoma.

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

“…In the present study, the ratios of p-Erk to Erk and of p-Raf1 (Ser388) to Raf1 were increased by doxycycline (1 µg/ml) treatment in CHL-X ( Figure 5B, 6B), indicating that HBx induced in CHL-X may activate c-Raf-1 down regulation and Erk activation. This result is consistent with the results of a previous study (Lee et al, 2001).…”

“…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).…”

Hepatitis B virus X protein promotes liver cell proliferation via a positive cascade loop involving arachidonic acid metabolism and p-ERK1/2

“…HBx is a transcriptional activator that can interact with a wide variety of regulatory elements, such as AP-1, AP-2, NF-κB and cAMP response element binding. Cytosolic HBx also participates in a wide range of signal transduction pathways (for example, the Akt, Wnt/β-catenin, NF-κB, Janus kinase/signal transducer and activator transcription factor (JAK/STAT) and Ras/Raf-mitogenactivated protein kinase (MAPK) pathways) [5][6][7][8].…”

X protein of hepatitis B virus functions as a transcriptional corepressor on the human telomerase promoter†

“…Interestingly, we found that HBx-3 could bind to MAZ but unexpectedly activate telomerase promoter and increase telomerase activity (data not shown) as previously reported. [35][36][37] The effects of different HBx proteins on hepatoma cells are contradictory; some have oncogenic properties [10][11][12][13][14] and some apoptotic. [52][53][54] Our study of HBx has provided evidence of both these properties, that is, HBx-3 is oncogenic and HBx-1 and HBx-2 are apoptotic.…”

“…7 HBx has been demonstrated to interfere with DNA repair 8,9 by which it may induce mutations in hepatocytes. In addition, HBx activates oncogenic signal transduction pathways, including the Jak-Stat, 10 Ras/MAP (mitogen-activated protein) kinase, 11 PI (phosphatidylinositol)-3 kinase/Akt, 11,12 SAPK/JNK (stress-activated protein kinase/c-Jun NH2-terminal kinase), 13 and NF-B (nuclear factor-kappa B) 14 pathways. Despite current molecular evidence suggesting that HBx is an oncoprotein, the detailed mechanism of HBx-mediated hepatocarcinogenesis remains to be determined.…”