The eukaryote genome constantly faces the threat of damage from exogenous and endogenous mutagens. Mammalian cells, therefore, have evolved an intricate network of defenses to maintain genomic stability. p53 is at the crossroads of these defense pathways. We investigate rare genomic instability and/or premature aging diseases, e.g., Bloom, Werner, Rothmund-Thomson, and Li-Fraumeni Syndromes, to gain insight into p53 function in the general population. For example, p53 cooperates with the Bloom Syndrome helicase, BLM, and the prorecombinogenic Rad51 during DNA replicative stress to act as a molecular governor of DNA recombination. We have also discovered transcriptional cofactors of p53, i.e., ING2-5, that enhance p53 effector functions in cell cycle checkpoints, apoptosis, and senescence. We plan to continue studying p53-mediated replicative senescence modulated by either ING family proteins or by POT1 and WRN that govern telomere attrition.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005795-10
Application #
7048111
Study Section
(LHC)
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2004
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Solomon, Hilla; Dinowitz, Nathan; Pateras, Ioannis S et al. (2018) Mutant p53 gain of function underlies high expression levels of colorectal cancer stem cells markers. Oncogene 37:1669-1684
Cooks, Tomer; Harris, Curtis C (2014) p53 mutations and inflammation-associated cancer are linked through TNF signaling. Mol Cell 56:611-2
Kumamoto, Kensuke; Fujita, Kaori; Kurotani, Reiko et al. (2009) ING2 is upregulated in colon cancer and increases invasion by enhanced MMP13 expression. Int J Cancer 125:1306-15
Unoki, Motoko; Kumamoto, Kensuke; Robles, Ana I et al. (2008) A novel ING2 isoform, ING2b, synergizes with ING2a to prevent cell cycle arrest and apoptosis. FEBS Lett 582:3868-74
Kumamoto, Kensuke; Spillare, Elisa A; Fujita, Kaori et al. (2008) Nutlin-3a activates p53 to both down-regulate inhibitor of growth 2 and up-regulate mir-34a, mir-34b, and mir-34c expression, and induce senescence. Cancer Res 68:3193-203
Shen, Jiang-Cheng; Unoki, Motoko; Ythier, Damien et al. (2007) Inhibitor of growth 4 suppresses cell spreading and cell migration by interacting with a novel binding partner, liprin alpha1. Cancer Res 67:2552-8
Yang, Qin; Zhang, Ran; Horikawa, Izumi et al. (2007) Functional diversity of human protection of telomeres 1 isoforms in telomere protection and cellular senescence. Cancer Res 67:11677-86
Hussain, S P; Schwank, J; Staib, F et al. (2007) TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene 26:2166-76
Koshiji, Minori; Kumamoto, Kensuke; Morimura, Keiichirou et al. (2007) Correlation of N-myc downstream-regulated gene 1 expression with clinical outcomes of colorectal cancer patients of different race/ethnicity. World J Gastroenterol 13:2803-10
Spillare, E A; Wang, X W; von Kobbe, C et al. (2006) Redundancy of DNA helicases in p53-mediated apoptosis. Oncogene 25:2119-23

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