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Path-Immuno - Nikolai Timchenko Lab

Houston, Texas

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Department of Pathology & Immunology - Timchenko Lab
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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).

Research Projects

There are three main projects in the lab:

  1. 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.
  2. 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.
  3. 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.

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