Huffington Center on Aging
Aging reduces proliferative capacities of liver by switching pathways of C/EBP a growth arrest
Nikolai A. Timchenko, Ph.D., received the award for his studies of molecular mechanisms that control regeneration in young and old livers. The liver is capable of completely regenerating itself in response to injury and after partial hepatectomy. It has been shown that the proliferative response to surgical resections is dramatically reduced in old livers. The understanding of the molecular basis for the reduced proliferative capacities of old livers is an important step in the development of therapeutic interventions to correct liver proliferation in elderly. Dr. Timchenko is working with the liver-specific C/EBP a protein and with the mechanisms by which this protein brings about growth arrest in the liver. Although C/EBP a is a transcription factor, it inhibits proliferation of young livers through direct interactions with cyclin dependent kinases. Dr. Timchenko’s lab has found that aging switches the liver-specific pathway of C/EBP a growth arrest to repression of E2F transcription. In old livers, the major portion of C/EBP a is observed in an age-specific C/EBP a -Rb-E2F4 complex that binds to E2F-dependent promoters and represses these genes. The repression of the E2F-dependent genes by the age-specific complex seems to be a major cause of the age-dependent loss of liver regenerative capacity.
Dr. Timchenko’s nomination was based on the following publications:
Wang H, Iakova P, Wilde M, Welm A, Goode T, Roesler WJ, Timchenko NA. C/EBPα arrests cell proliferation through direct inhibition of Cdk2 and Cdk4. Mol Cell. 2001 Oct;8(4):817-28.
Iakova P, Awad SS, Timchenko NA. Aging reduces proliferative capacities of liver by switching pathways of C/EBPalpha growth arrest. Cell. 2003 May 16;113(4):495-506.
Wang GL, Iakova P, Wilde M, Awad S, Timchenko NA. Liver tumors escape negative control of proliferation via PI3K/Akt-mediated block of C/EBP alpha growth inhibitory activity. Genes Dev. 2004 Apr 15;18(8):912-25.