The major focus of this proposal is to understand the tumor suppressive properties of prohibitin, a gene located on human chromosome 17q21 close to the BRACA1 locus. Prohibitin can induce a G1/S arrest in cells, and prohibitin mutations have been found in a subset of sporadic breast cancers. No information is available on the mechanisms by which prohibitin induces a G1/S arrest. Our recent studies have shown that prohibitin can physically interact with the Rb family proteins, as well as Raf- 1, a vital signaling molecule. Prohibitin is capable of suppressing the formation of colonies in a variety of cell lines; this suppression can be reversed by Raf-1. Further, prohibitin can repress the transcriptional activity of E2F, a major down- stream target of the Rb protein. Prohibitin mediated repression of E2F activity in B-cell lines can be reversed by stimulating the IgM receptors. The experiments proposed in this application aim at understanding the molecular mechanisms by which prohibitin induces growth arrest in cells. A detailed mutational analysis of prohibitin will be conducted, to identify the region of prohibitin involved in effecting growth suppression, response to Raf-1 protein as well as inhibition of E2F activity. The mechanisms involved in prohibitin-mediated repression of E2F will be studied in detail, with special emphasis on the role of HDAC1 in this process. Attempts will also be made to understand how prohibitin function is regulated by upstream signals, especially Raf-1 and MAP kinase pathway. In the same context, the role of prohibitin in IgM receptor-mediated signaling will be established. Lastly, we will assess the status of prohibitin gene and protein in human tumors and tumor derived cell lines. We will focus on the role of prohibitin inactivation in breast carcinomas as well as B-cell lymphomas, and it will be assessed whether the mutation has contributed to a loss of growth control. We believe that the studies described in this proposal will throw light on the role of a poorly understood tumor suppressor gene in oncogenesis, and will identify novel targets for designing anti-cancer agents.
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