Nikolai A. Timchenko, Ph.D.
Ph.D 1984. St. Petersburg Institute of Experimental
Medicine, Russia
Associate Professor of Pathology & Huffington Center
on Aging
Baylor College of Medicine, Building: Alkek Tower,
Room: ALKT-N803
Phone: 713.798.1567
E~mail: nikolait@bcm.tmc.edu
RESEARCH INTERESTS:
My laboratory investigates a molecular basis for the loss of proliferative capacities in liver of old animals. The elucidation 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 older organisms. Our studies are primarily focused on a family of transcription factors, C/EBP, that play a crucial role in the regulation of liver growth and differentiation. We found that one of the members of C/EBP family, C/EBPa, arrests liver proliferation by direct inhibiting cdk2 and cdk4. The mechanisms of this inhibition involve direct protein-protein interactions and do not depend on the transcriptional activity of C/EBPa. Recently we found that aging switches the growth inhibitory pathway of C/EBPa from inhibiting cdks to repression of E2F transcription. In old livers, C/EBPa forms a high MW C/EBPa-Rb-E2F4 complex which binds to E2F promoters and represses E2F transcription. Our data suggest that old livers are not able to proliferate after partial hepatectomy, since the cascade of gene expression after PH lacks pathways capable of eliminating the C/EBPa-mediated E2F repression.
The second direction in my lab is the investigation of the role of RNA binding proteins in the regulation of cell growth, differentiation and replicative senescence. We found that RNA binding proteins regulate the expression of cell cycle proteins via direct interaction with corresponding mRNAs. CUG-triplet repeat binding protein, CUGBP1, binds to mRNAs coding for C/EBPb and for p21 and controls translation of these mRNAs. We identified a new RNA binding protein, calreticulin (CRT), which also interacts with the 5' regions of p21 and C/EBPb mRNAs. Our recent data show that the competition of CUGBP1 and CRT for the regulation of p21 translation determines whether cells proliferate or develop a senescent phenotype. In young fibroblasts, CRT binds to the 5'region of p21 mRNA and blocks p21 translation. In senescent fibroblasts, CUGBP1 is activated and replaces CRT from p21 mRNA leading to an increase of p21 translation. Our data suggest that this competition determines cell fate.
Research in my lab is supported by two NIH R01 awards and by PPG award (PI - Dr. J. Smith., Project Leader - Timchenko Nikolai A).
Selected Publications
Welm, A.L., Mackey, S.L., Timchenko, L.T., Darlington G.J., and Timchenko N.A. Translational induction of LIP during acute phase response leads to repression of C/EBP alpha mRNA. J Biol Chem., 275:27406-27413, 2000.
Timchenko, N.A., Iakova, P., Cai, Z-J., Smith, J.R. and Timchenko, L.T. Molecular basis for impaired cell cycle withdrawal in myotonic dystrophy. Mol. Cell. Biol. v21:6927-6938, 2001.
Wang, H., Wilde, M., Iakova, P., Welm, A., Goode, T., Roesler, W. J., and Timchenko, N.A. C/EBPa arrests cell proliferation through direct inhibition of cdk2 and cdk4. Molecular Cell, 8: 817-828, 2001.
Wang, H., Goode, T., Iakova, P. Albrecht, J. and Timchenko N.A. "C/EBPa triggers proteasome-dependent degradation of cdk4 during growth arrest. EMBO J. 21:930-941, 2002.
Timchenko, L.T., Iakova, P., Welm, L.A., Cai Z-J. and Timchenko, N.A. Calreticulin interacts with C/EBPa and C/EBPb mRNAs and represses translation of C/EBP proteins. Mol Cell Biol. 22:722-7257, 2002.
Iakova, P., Awad, S.S. and Timchenko N.A. Aging reduces proliferative capacities of liver by switching pathways of C/EBPa growth arrest. Cell 113:495-506, 2003.