Hepatitis B virus X protein enhances the transcriptional activity of the androgen receptor through c-Src and glycogen synthase kinase-3beta kinase pathways.
Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) occurs predominantly in men. By enhancing the transcriptional activity of the androgen receptor (AR) gene in a ligand-dependent manner, the HBV X protein (HBx) might contribute to this disparity between sexes. To dissect the mechanisms underlying HBx-enhanced AR transactivation, we investigated the effect of HBx on two critical steps in the regulation of ligand-stimulated AR activities. One step is the dimerization of AR (through the interaction of its N-termini and C-termini), and the other step is the activation of the AR N-terminal transactivation domain (NTD). HBx increased the NTD activation of the AR through c-Src kinase. HBx also enhanced AR dimerization by inhibiting glycogen synthase kinase-3beta (GSK-3beta) activity, which acts as a negative regulator of the interaction between AR and the N-termini and C-termini. The HBx-enhanced AR transactivation was abolished by blocking c-Src and activating GSK-3beta kinases simultaneously, suggesting that these two kinases act as major switches in the activation process. The regulatory function of both kinases has been further verified in primary hepatocytes isolated from the livers of HBx transgenic male mice.


CONCLUSIONS
Our study thus identified two key kinases through which HBx enhances the AR transcriptional activity. These kinases might be potential candidates for future prevention or therapy for HBV-related HCC in men.
Yang
Wan-Jen
WJ
Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan.
Chang
Ching-Ju
CJ
Yeh
Shiou-Hwei
SH
Lin
Wei-Hsiang
WH
Wang
Sheng-Han
SH
Tsai
Ting-Fen
TF
Chen
Ding-Shinn
DS
Chen
Pei-Jer
PJ
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006509:Hepatitis B / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D012727:Sex Characteristics; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D054334:Viral Regulatory and Accessory Proteins / Q000378:metabolism*; D019061:src-Family Kinases
D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3