Aging reduces proliferative capacities of liver by switching pathways of C/EBPalpha growth arrest.
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.
Iakova
Polina
P
Huffington Center on Aging, Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
Awad
Samir S
SS
Timchenko
Nikolai A
NA
D000375:Aging / Q000378:metabolism*; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050704:E2F4 Transcription Factor; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005809:Genes, Regulator / Q000235:genetics; D016259:Genes, myc / Q000235:genetics; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology*; D008099:Liver / Q000166:cytology / Q000201:enzymology* / Q000254:growth & development*; D008115:Liver Regeneration / Q000235:genetics*; D046911:Macromolecular Substances; D008970:Molecular Weight; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D022763:CCAAT-Enhancer-Binding Protein-alpha; D004268:DNA-Binding Proteins; D050704:E2F4 Transcription Factor; D046911:Macromolecular Substances; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D018844:Cyclin-Dependent Kinases