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Cell Cycle, Cell Death, and Senescence

Hepatitis B Virus Pre-S₂ Mutant Surface Antigen Induces Degradation of Cyclin-Dependent Kinase Inhibitor p27^Kip1 through c-Jun Activation Domain-Binding Protein 1

Departments of ¹ Basic Medical Sciences, ² Microbiology and Immunology, ³ Biochemistry, ⁴ Medical Laboratory Science and Biotechnology, ⁵ Center for Gene Regulation and Signal Transduction Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan and ⁶ Division of Clinical Research, National Health Research Institute, Taipei, Taiwan

Requests for reprints: Wenya Huang, Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan. Phone: 886-6-235-3535, ext. 5766; Fax: 886-6-236-3956. E-mail: whuang{at}mail.ncku.edu.tw

The hepatitis B virus (HBV) large surface antigen (LHBS) mutant with deletion at the pre-S₂ region accumulates in endoplasmic reticulum (ER) and is associated with HBV-induced hepatocellular carcinogenesis. In this study, we found that the pre-S₂ LHBS mutant directly interacts with the Jun activation domain–binding protein 1 (JAB1). Association of pre-S₂ LHBS with JAB1 dissociated JAB1 from the JAB1/IRE1 complex in ER. The free (active) JAB1 then translocated into cell nuclei and rendered the Cdk inhibitor p27^Kip1 to cytosolic proteasome for degradation. The pre-S₂ LHBS mutant induced hyperphosphorylation of tumor suppressor retinoblastoma (RB) via cyclin-dependent kinase 2 (Cdk2), a downstream molecule regulated by p27^Kip1. This effect is independent of the ER stress signaling pathway. The transgenic mice carrying the pre-S₂ mutant LHBS gene also exhibited Cdk2 activation, p27^Kip1 degradation, as well as RB hyperphosphorylation. The mouse hepatocytes exhibited morphologic abnormalities such as chromatin condensation, multinucleation, and dysplasia of hepatocytes. In summary, the pre-S₂ LHBS mutant causes p27^Kip1 degradation through direct interaction with JAB1. The pre-S₂ mutant LHBS is suggested to be a potential oncoprotein for HBV-related hepatocellular carcinoma. (Mol Cancer Res 2007;5(10):1063–72)