Mice lacking bi-1 gene show accelerated liver regeneration

The liver has enormous regenerative capacity such that, after partial hepatectomy, hepatocytes rapidly replicate to restore liver mass, thus providing a context for studying in vivo mechanisms of cell growth regulation. Bax inhibitor-1 (BI-1) is an evolutionarily conserved endoplasmic reticulum (ER) protein that suppresses cell death. Interestingly, the BI-1 protein has been shown to regulate Ca²⁺ handling by the ER similar to antiapoptotic Bcl-2 family proteins. Effects on cell cycle entry by Bcl-2 family proteins have been described, prompting us to explore whether bi-1-deficient mice display alterations in the in vivo regulation of cell cycle entry using a model of liver regeneration. Accordingly, we compared bi-1^+/+ and bi-1 ^-/- mice subjected to partial hepatectomy with respect to the kinetics of liver regeneration and molecular events associated with hepatocyte proliferation. We found that bi-1 deficiency accelerates liver regeneration after partial hepatectomy. Regenerating hepatocytes in bi-1^-/- mice enter cell cycle faster, as documented by more rapid incorporation of deoxynucleotides, associated with earlier increases in cyclin D1, cyclin D3, cyclin-dependent kinase (Cdk) 2, and Cdk4 protein levels, more rapid hyperphosphorylation of retinoblastoma protein, and faster degradation of p27^Kip1. Dephosphorylation and nuclear translocation of nuclear factor of activated T cells 1 (NFAT1), a substrate of the Ca²⁺- sensitive phosphatase calcineurin, were also accelerated following partial hepatectomy in BI-1-deficient hepatocytes. These findings therefore reveal additional similarities between BI-1 and Bcl-2 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 cell survival.