Aging reduces proliferative capacities of liver by switching pathways of C/EBPalpha growth arrest

Cell. 2003 May 16;113(4):495-506. doi: 10.1016/s0092-8674(03)00318-0.

Abstract

The liver is capable of completely regenerating itself in response to injury and after partial hepatectomy. In liver of old animals, the proliferative response is dramatically reduced, the mechanism for which is unknown. The liver specific protein, C/EBPalpha, normally arrests proliferation of hepatocytes through inhibiting cyclin dependent kinases (cdks). We present evidence that aging switches the liver-specific pathway of C/EBPalpha growth arrest to repression of E2F transcription. We identified an age-specific C/EBPalpha-Rb-E2F4 complex that binds to E2F-dependent promoters and represses these genes. The C/EBPalpha-Rb-E2F4 complex occupies the c-myc promoter and blocks induction of c-myc in livers of old animals after partial hepatectomy. Our results show that the age-dependent switch from cdk inhibition to repression of E2F transcription causes a loss of proliferative response in the liver because of an inability to induce E2F target genes after partial hepatectomy providing a possible mechanism for the age-dependent loss of liver regenerative capacity.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging / metabolism*
  • Animals
  • CCAAT-Enhancer-Binding Protein-alpha / genetics
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism*
  • Cell Division / genetics
  • Cyclin-Dependent Kinases / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • E2F4 Transcription Factor
  • Gene Expression Regulation, Developmental / genetics
  • Genes, Regulator / genetics
  • Genes, myc / genetics
  • Hepatocytes / cytology
  • Hepatocytes / enzymology*
  • Liver / cytology
  • Liver / enzymology*
  • Liver / growth & development*
  • Liver Regeneration / genetics*
  • Macromolecular Substances
  • Molecular Weight
  • Promoter Regions, Genetic / genetics
  • Rats
  • Rats, Inbred F344
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Retinoblastoma Protein / genetics
  • Retinoblastoma Protein / metabolism
  • Signal Transduction / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • CCAAT-Enhancer-Binding Protein-alpha
  • DNA-Binding Proteins
  • E2F4 Transcription Factor
  • Macromolecular Substances
  • Repressor Proteins
  • Retinoblastoma Protein
  • Transcription Factors
  • Cyclin-Dependent Kinases