Synergism between p53 and Mcl-1 in protecting from hepatic injury, fibrosis and cancer
Journal
Journal of Hepatology
Journal Volume
54
Journal Issue
4
Pages
685-694
Date Issued
2011
Author(s)
Weng S.-Y.
Yang C.-Y.
Li C.-C.
Sun T.-P.
Tung S.-Y.
Yen J.J.-Y.
Tsai T.-F.
Chen C.-M.
Chen S.H.
Hsiao M.
Yang-Yen H.-F.
Abstract
Background & Aims: Mcl-1-deficient hepatocytes are prone to undergo apoptosis. The tumor suppressor protein p53 plays an important role in apoptosis control as well as other cellular responses. This study was initially aimed to examine whether p53 was involved in Mcl-1 deficiency-induced apoptosis of hepatocytes. Methods: Hepatocyte-specific Mcl-1 knockout (Alb-Mcl-1 -/-) mice and Alb-Mcl-1-/- mice in wild-type or p53-deficient background were generated and characterized. Results: Alb-Mcl-1-/- mice were viable, but their liver cells were prone to undergo apoptosis and manifested a slightly elevated level of p53. To examine the role of p53 in Alb-Mcl-1-/- livers, Alb-Mcl-1-/- mice without p53 (DKO mice) were characterized. Unexpectedly, although p53-deficient mice appeared to be developmentally normal, DKO mice were highly susceptible to neonatal death (?60%). Further analysis revealed that such an early lethality was likely due to hepatic failure caused by a marked reduction of fully-differentiated hepatocytes at the perinatal/neonatal stage. Moreover, those DKO mice that did survive to adulthood manifested more severe liver damage than Alb-Mcl-1-/- mice, suggesting that p53 was activated in Alb-Mcl-1-/- livers to promote cell survival. Microarray followed by quantitative PCR analysis suggested that p21Waf1/Cip1, one p53 target gene with apoptosis-inhibitory function, is likely involved in the protective role of p53 in Alb-Mcl-1-/- livers. Moreover, we demonstrated that loss of p53 promoted liver fibrosis and tumor development in Alb-Mcl-1 -/- mice. Conclusions: This study revealed an unexpected synergism between Mcl-1 and p53 in protecting from hepatic injury, fibrosis, and cancer. ? 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
SDGs
Other Subjects
alanine aminotransferase; aspartate aminotransferase; protein mcl 1; protein p53; alanine aminotransferase blood level; animal cell; animal experiment; apoptosis; article; aspartate aminotransferase blood level; cell proliferation; cell survival; cell viability; controlled study; immunoblotting; immunohistochemistry; liver cancer; liver fibrosis; liver injury; liver protection; liver regeneration; liver resection; liver tumor; mouse; newborn death; nonhuman; priority journal; protein expression; protein function; protein protein interaction; Animals; Apoptosis; Base Sequence; Cell Proliferation; DNA Primers; Female; Genes, p53; Hepatocytes; Liver; Liver Cirrhosis, Experimental; Liver Neoplasms, Experimental; Male; Mice; Mice, Knockout; Mice, Transgenic; Pregnancy; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53
Type
journal article