Title:
RB functions in rewiring metabolic pathways in cancer cells

Chiaki Takahashi
Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University

Abstract:
　The RB tumor suppressor gene has been implicated primarily in the control of cell cycle and terminal differentiation. However, recent studies indicate that pRB may possess much more variety of functions than previously thought. We have been exploring unique functions of pRB using mice with various genetic backgrounds. Rb-heterozygous mice generate thyroid C cell adenoma showing multiple evidences of DNA damage response and cellular senescence. Additional deletion of N-ras as well as senescence or DNA damage response-related genes including Ink4a, Arf, Trp53, Suv39h1 or ATM rendered cancellation to all these evidences, and allowed C cell adenoma to progress to highly malignant adenocarcinoma. We then determined the mechanism by which N-ras counteracts RB-deficient carcinogenesis. An unbiased assay demonstrated that pRB targets isoprenylation enzymes in a way dependent on E2F/SREBP transcription factors and independent of cell cycle regulation. Since this discovery, by employing in vitro experimental models to address the roles of pRB in controlling undifferentiated status exhibited by a subpopulation of tumor cells, we have linked RB functions to mevalonate pathway, fatty acid metabolism, glycolysis, mitochondrial function and glutamine metabolism. In this talk, I will introduce unprecedented functions of pRB especially in cooperation with p53 in rewiring metabolic pathways in cancer cells.

References:
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4. Takahashi C et al., Nature Genet. 38: 118-123, 2006.