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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090522-03
Application #
6633984
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Okano, Paul
Project Start
2001-04-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
3
Fiscal Year
2003
Total Cost
$253,980
Indirect Cost
Name
University of Cincinnati
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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Kanai, Masayuki; Hanashiro, Kazuhiko; Kim, Song-Hee et al. (2007) Inhibition of Crm1-p53 interaction and nuclear export of p53 by poly(ADP-ribosyl)ation. Nat Cell Biol 9:1175-83
Kanai, Masayuki; Ma, Zhiyong; Izumi, Hideki et al. (2007) Physical and functional interaction between mortalin and Mps1 kinase. Genes Cells 12:797-810
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Ma, Z; Izumi, H; Kanai, M et al. (2006) Mortalin controls centrosome duplication via modulating centrosomal localization of p53. Oncogene 25:5377-90

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