Chromosome instability (and resulting aneuploidy) has been recognized as a hallmark of cancer and contributes to multi-step carcinogenesis by facilitating the accumulation of genetic lesions required for the acquisition of various malignant phenotypes. However, much remains to be learned regarding the causes and mechanisms of chromosome instability in cancer. We have recently found that p53 tumor suppressor protein, the product of the most commonly mutated genes in human cancers, is involved in the control of the centrosome duplication cycle. Loss or mutational inactivation of p53 results in uncontrolled amplification of centrosomes. A deleterious consequence of centrosome hyperamplification is most prominently featured during mitosis by the formation of aberrant spindles organized by multiple centrosomes (spindle poles), leading to an increased frequency of chromosome segregation errors. Moreover, centrosome hyperamplification is commonly observed in human cancers, and that the occurrence of centrosome hyperamplification in those tumors is strongly correlated with loss or mutational inactivation of p53. This suggests that centrosome hyperamplification induced by mutation of p53 is one major factor that contributes to chromosome instability in human cancers. The goal of this research proposal is to elucidate the molecular mechanisms that control initiation of centrosome duplication, coordination of the centrosome and DNA duplication cycles, and suppression of centrosome reduplication within a single cell cycle. Elucidation of this unexplored function of p53 at a molecular level will provide vital information for fully understanding the tumor suppressor activity of p53, the role of p53 mutation in carcinogenesis, and also for designing effective cancer intervention protocols targeting p53 to block centrosome duplication. Such an approach may prove effective in cancer intervention, since centrosome duplication, like DNA replication, is restricted to proliferating cells. Moreover, blocking the centrosome duplication process results in suppression of chromosome instability as well as cell division.
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