The tumor suppressor p53 is structurally or functionally inactivated in most human tumors. In those tumors that retain intact p53, p53 signaling is often inactivated through altered expression of other molecules. An example of this p53 functional inactivation occurs in a fraction of human sarcomas, in which amplification and overexpression of the oncogene mdm2 results in p53 degradation. Two recent reports in the literature implicate another potential oncogene that may inactivate p53 in human breast and prostate cancers. This gene, encoding the wildtype p53-induced phosphatase wip1 or Ppm1 d). is amplified and overexpressed in 16% of human breast cancers. It is the only consistently amplified gene in these breast cancers that shows transforming activity in in vitro transformation assays. Wipl is induced by p53 following ionizing or ultraviolet radiation and it has been shown to dephosphorylate p38 MAP kinase, inactivating it and inhibiting p38 activation of p53 through phosphorylation. It is hypothesized that Wipl forms part of a negative regulatory feedback loop that indirectly inhibits p53 function following initial activation of p53. Thus, amplification of Wipl in human tumors could cause increased inhibition of p53 signaling and promote tumorigenesis through p53-dependent mechanisms. A major goal of this proposal is to use in vitro culture systems and animal models (including a Wipl knockout mouse that our laboratory has generated) to test the oncogenicib, of Wip1 in multiple contexts. We will determine whether the absence of Wipl confers a tumor resistance phenotype through increased p53 activity. We will also examine whether Wipl has p53-independent effects in enhancement of transformation or tumorigenesis and which domains of Wipl are crucial for transformation-related effects. A second major goal of this proposal is to identify normal cell signaling pathways influenced by Wipl in an attempt to understand the normal biological functions of this phosphatase. Wip1-interacting proteins will be identified and their relationship to Wipl will be explored. Our overall goal is to better understand the molecular mechanisms by which this putative human oncogene affects both normal and oncogenic cell signaling.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100420-05
Application #
7215579
Study Section
Pathology B Study Section (PTHB)
Program Officer
Blair, Donald G
Project Start
2003-04-01
Project End
2008-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
5
Fiscal Year
2007
Total Cost
$254,008
Indirect Cost
Name
Baylor College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Darlington, Y; Nguyen, T-A; Moon, S-H et al. (2012) Absence of Wip1 partially rescues Atm deficiency phenotypes in mice. Oncogene 31:1155-65
Reddy, Jay P; Peddibhotla, Sirisha; Bu, Wen et al. (2010) Defining the ATM-mediated barrier to tumorigenesis in somatic mammary cells following ErbB2 activation. Proc Natl Acad Sci U S A 107:3728-33
Moon, Sung-Hwan; Nguyen, Thuy-Ai; Darlington, Yolanda et al. (2010) Dephosphorylation of ?-H2AX by WIP1: an important homeostatic regulatory event in DNA repair and cell cycle control. Cell Cycle 9:2092-6
Liu, Hongbing; Herrmann, Christine H; Chiang, Karen et al. (2010) 55K isoform of CDK9 associates with Ku70 and is involved in DNA repair. Biochem Biophys Res Commun 397:245-50
Moon, Sung-Hwan; Lin, Lin; Zhang, Xinna et al. (2010) Wild-type p53-induced phosphatase 1 dephosphorylates histone variant gamma-H2AX and suppresses DNA double strand break repair. J Biol Chem 285:12935-47
Nguyen, Thuy-Ai; Slattery, Scott D; Moon, Sung-Hwan et al. (2010) The oncogenic phosphatase WIP1 negatively regulates nucleotide excision repair. DNA Repair (Amst) 9:813-23
Hinkal, George W; Gatza, Catherine E; Parikh, Neha et al. (2009) Altered senescence, apoptosis, and DNA damage response in a mutant p53 model of accelerated aging. Mech Ageing Dev 130:262-71
Lu, Xiongbin; Nguyen, Thuy-Ai; Moon, Sung-Hwan et al. (2008) The type 2C phosphatase Wip1: an oncogenic regulator of tumor suppressor and DNA damage response pathways. Cancer Metastasis Rev 27:123-35
Castellino, Robert C; De Bortoli, Massimiliano; Lu, Xiongbin et al. (2008) Medulloblastomas overexpress the p53-inactivating oncogene WIP1/PPM1D. J Neurooncol 86:245-56
Nannenga, Bonnie; Lu, Xiongbin; Dumble, Melissa et al. (2006) Augmented cancer resistance and DNA damage response phenotypes in PPM1D null mice. Mol Carcinog 45:594-604

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