Nikolai A. Timchenko Laboratory
Dr. Timchenko laboratory investigates molecular mechanisms by which aging reduces liver functions and mechanisms of liver cancer. Primary focus of the studies is a family of transcription factors, CCAAT/Enhancer Binding Proteins (C/EBP).
There are three main projects in the lab:
- The first project examines the role C/EBP proteins in chromatin remodeling and in the age-associated liver dysfunctions. We have recently shown the critical role of C/EBPα -mediated chromatin remodeling in the age-associated dysfunctions of the liver and in the maintenance of physiological homeostasis. We found that ph-S193 isoform of C/EBPα is increased in livers of old mice; therefore, we have generated C/EBPα-S193D knockin mice which mimic the ph-S193 isoform of C/EBPα. Analyses of these mice showed that phosphorylation of C/EBPα at S193 leads to the appearance of heterochromatin regions which causes the development of age-related dysfunctions of the liver.
- The second project investigates molecular mechanisms of liver cancer. Phosphorylation of C/EBPα at serine 193 (S193-ph) is up-regulated in older mice which have increased frequency of liver cancer. Therefore, we investigated the role of S193-ph in the development of liver cancer using knockin mice expressing a phospho-mimetic aspartic acid residue in place of serine at position 193 (S193D) of C/EBPα. The treatment of these mice with diethylnitrosamine (DEN), which induces formation of liver cancer, resulted in earlier development of liver tumors due to specific degradation of S193D isoform of C/EBPα through the ubiquitin-proteasome system (UPS). We found that gankyrin, a small subunit of 26S proteasome, interacts with the S193-ph isoform of C/EBPα and target it for UPS-mediated degradation. We are investigating mechanisms by which liver cancer activates gankyrin with the goal to develop therapeutic approaches to prevent cancer.
- The third project investigates the role of alterations of translation in the age-associated loss of regenerative capacities of livers. We have found that aging activates translational complex CUGBP1-eIF2 which binds to the 5’ regions of several mRNAs and increases translation. These mRNAs include HDAC1 and C/EBPß mRNAs. Our data demonstrate that translational induction of HDAC1 in old livers leads to association of HDAC1 with the C/EBPα-Brm complex and is involved in the age-dependent loss of regenerative capacities of the liver. We are now searching for the additional targets of the CUGBP1-eIF2 complex which are altered in livers of old mice.