Abstract B17: Synergism between p53 and Mcl-1 in hepatocyte maturation and survival

Abstract

Mcl-1 plays an apical role in many cell survival programs. Mice without Mcl-1 die at early embryonic stage. A conditional knockout approach has thus been employed to study Mcl-1 functions in the liver. Mice without Mcl-1 in hepatocytes (Alb-Mcl-1 −/−) were viable but manifested some defects in the mature liver, including enlarged cell size, enhanced apoptosis and proliferation of liver cells. An increased level of p53 was also observed in adult Alb-Mcl-1 −/− mouse livers. We thus generated Alb-Mcl-1 −/− mice in p53-deficient background to examine whether p53 was involved in Mcl-1 deficiency-induced hepatocyte apoptosis. Loss of p53 in Alb-Mcl-1 −/− mice (DKO mice) resulted in a very high frequency of neonatal death. Further analysis revealed that such early lethality was likely due to hepatic failure caused by a marked reduction of fully-differentiated hepatocytes at the perinatal/neonatal stage. On the other hand, those DKO mice that did survive to adulthood manifested much more severe liver cell damage than Alb-Mcl-1 −/−mice of the same age, suggesting that p53 is activated in Alb-Mcl-1 −/− livers to help resolve Mcl-1 deficiency-induced hepatocyte damage. Last, we demonstrated that p53 enhanced-hepatocyte survival is a cell-autonomous effect, and that such effect is mediated in part through transcriptional up-regulation of p21 Waf1/Cip1 in Alb-Mcl-1 −/− livers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B17.