Mechanism of cell growth deregulation during oncogenesis
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- Ph.D., 1982, Calcutta University, India
The research interest of my laboratory is to understand the growth regulatory mechanisms of normal cells particularly the ones that are deregulated during oncogenesis. At present, my laboratory is focused to understand the mechanism of oncogenesis induced by an oncoprotein coded by the human homologue of mouse double minute 2 (hmdm2) gene. The hmdm2 gene product (hMDM2) frequently overexpresses in malignant human tumors. The oncoprotein forms complex with the tumor suppressor p53 and inhibits p53-mediated transcriptional activation. It also interacts with simian virus 40 T antigen in the absence of p53. The hmdm2 gene is evolutionarily conserved among eukaryotes, which suggests that the gene product serve an important function in eukaryotic cells. Several hMDM2-related polypeptides have been found in cultured mouse or human tumorigenic cells that overexpress the protein. It is not known which of these forms induce tumorigenesis. Amplification of the entire mdm2 gene capable of expressing all the spliced forms was shown to enhance tumorigenic potential of murine cells.
Recent work from our laboratory shows that overexpression of the full-length hMDM2 from its cDNA arrests the G1 to S phase transition of normal human or murine cells. Elimination of the growth inhibitory domains of the oncoprotein induces tumorigenesis. Some cancer-derived cell lines are partially insensitive to hMDM2-mediated growth arrest. These observations suggest that normal cells induce full-length hMDM2 in response to oncogenic challenges to protect against premature cell cycle progression. If the oncoprotein is defective in growth arrest or if the cells are insensitive to hMDM2-mediated growth arrest, premature progression of cell cycle may lead to tumorigenesis. Thus hMDM2 may be a target of viral transforming proteins such as T antigen.
At present, our goal is to understand the normal biological function of the hMDM2 oncoprotein and how its overexpression is involved in the etiology of cancer. We are in the process of analyzing the growth regulatory properties of full-length hMDM2 as well as the forms of hMDM2 overexpressed in cancer cells. We are interested to determine the biochemical mechanism of hMDM2-mediated growth regulation.