Data from Mice Lacking <i>bi-1</i> Gene Show Accelerated Liver Regeneration

Abstract

<div>Abstract<p>The liver has enormous regenerative capacity such that, after partial hepatectomy, hepatocytes rapidly replicate to restore liver mass, thus providing a context for studying <i>in vivo</i> 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 Ca<sup>2+</sup> 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 <i>bi-1</i>–deficient mice display alterations in the <i>in vivo</i> regulation of cell cycle entry using a model of liver regeneration. Accordingly, we compared <i>bi-1</i><sup>+/+</sup> and <i>bi-1</i><sup>−/−</sup> mice subjected to partial hepatectomy with respect to the kinetics of liver regeneration and molecular events associated with hepatocyte proliferation. We found that <i>bi-1</i> deficiency accelerates liver regeneration after partial hepatectomy. Regenerating hepatocytes in <i>bi-1</i><sup>−/−</sup> 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<sup>Kip1</sup>. Dephosphorylation and nuclear translocation of nuclear factor of activated T cells 1 (NFAT1), a substrate of the Ca<sup>2+</sup>-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 <i>in vivo</i>, in addition to its previously described actions as a regulator of cell survival. [Cancer Res 2007;67(4):1442–50]</p></div>