2582

Bax Inhibitor-1 (BI-1) is an evolutionarily conserved ER protein that was identified as a suppressor of Bax-induced cell death in a yeast-based screen (Xu & Reed, Mol Cell 1: 337, 1998) and that has the ability to suppress cell death in both animal and plant cells. Interestingly, the BI-1 protein has been shown to regulate Ca2+ handling by the ER, as described for several Bcl-2-family proteins which also reside at least in part in ER membranes, where they appear to control levels of releasable Ca2+ in this organelle. Moreover, an effect on cell cycle entry by Bcl-2/Bcl-xL family proteins has been described. These observations with Bcl-2/Bax family proteins therefore prompted us to explore whether bi-1-deficient mice display alterations in liver regeneration. Accordingly, we compared bi-1 (+/+) and bi-1 (−/−) mice subjected to partial hepatectomy (PH) with respect to the kinetics of liver regeneration, and associated events of hepatocyte proliferation, induction of cyclins, phosphorylation of Rb, and other molecular events. We report here that bi-1 regulates hepatocyte proliferation in vivo following PH. We demonstrated that bi-1-deficiency accelerates liver regeneration after PH. Regenerating hepatocytes of bi-1-deficient mice enter cell cycle faster, as documented by more rapid accumulation of BrdU-incorporating cells, associated with earlier increases in Cyclin D1, Cyclin D3, Cdk-2 and Cdk-4 protein levels, more rapid hyperphosphorylation of RB, and faster degradation of p27kip1. Ablation of bi-1 however does not disturb the homeostatic mechanisms that signal for cessation of hepatocyte proliferation once liver size has been restored, as liver weights of bi-1−/− mice did not exceed normal values after completion of regeneration. Altogether therefore this study of the effects of bi-1 deficiency on liver regeneration reveals additional similarities between BI-1 and Bcl-2/Bax-family proteins, showing a role for BI-1 in regulating cell proliferation in vivo, in addition to its previously described actions as a regulator of apoptosis. While much remains to be learned about the molecular mechanisms involved, elucidation of the signaling pathways modulated by BI-1 may provide new insights for improved understanding and possibly treatment of proliferative and degenerative diseases.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]