title: Synergism between p53 and Mcl-1 in protecting from hepatic injury, fibrosis and cancer.
abstract: OBJECTIVE
  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 p21(Waf1/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.
authors.affiliation: Institute of Molecular Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Shih-Yen
authors.initials: SY
authors.lastname: Weng
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Yang
authors.forename: Chao-Chin
authors.initials: CC
authors.lastname: Li
authors.forename: Te-Ping
authors.initials: TP
authors.lastname: Sun
authors.forename: Shu-Yun
authors.initials: SY
authors.lastname: Tung
authors.forename: Jeffrey Jong-Young
authors.initials: JJ
authors.lastname: Yen
authors.forename: Ting-Fen
authors.initials: TF
authors.lastname: Tsai
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Chen
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.forename: Pei-Hsin
authors.initials: PH
authors.lastname: Huang
authors.forename: Hsin-Fang
authors.initials: HF
authors.lastname: Yang-Yen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001483:Base Sequence; D049109:Cell Proliferation; D017931:DNA Primers / Q000235:genetics; D005260:Female; D016158:Genes, p53; D022781:Hepatocytes / Q000473:pathology / Q000502:physiology; D008099:Liver / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011247:Pregnancy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D017931:DNA Primers; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53