This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our long-term goal is to understand the roles of protein phosphatases in regulating p53 signaling pathway during DNA damage response and tumorigenesis. In this proposal, we will concentrate on the regulation of MdmX-p53 auto-regulatory feedback loop by protein phosphatases. MdmX inhibits the transcriptional activity of the tumor suppressor p53 that is induced by DNA damage or oncogenic stresses. Overexpression of MdmX and aberrant p53 regulation lead to deregulated cell growth and contribute to tumorigenesis. High levels of MdmX associate with 24.6% of various human cancers. In particular, MdmX is overexpressed in 18.5% of human colorectal cancers. Thus, MdmX must be tightly controlled in cells. Recently, we have identified Wip1, a ser/thr protein phosphatase, as a homeostatic regulator of MdmX. Our recent studies demonstrated that Wip1 directly dephosphorylates MdmX at the ATM-targeted Ser403. Wip1 inhibits the DNA damage-induced ubiquitination and degradation of MdmX, leading to the stabilization of MdmX and reduction of p53 activities. In addition to Wip1, three isoforms of Protein Phosphatase 1 (PP1) have also been identified as positive regulators for MdmX. In light of these exciting findings, we hypothesize that protein phosphatases may play a physiological role in the regulation of the MdmX-p53 pathway. Hence, we will use in vivo and intro approaches to systematically investigate this previously untested hypothesis in this proposal.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
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Special Emphasis Panel (ZRR1-RI-5 (01))
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University of South Carolina at Columbia
Schools of Arts and Sciences
United States
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Oliver, David; Ji, Hao; Liu, Piaomu et al. (2017) Identification of novel cancer therapeutic targets using a designed and pooled shRNA library screen. Sci Rep 7:43023
Mentrup, Heather L; Hartman, Amanda; Thames, Elizabeth L et al. (2017) The ubiquitin ligase ITCH coordinates small intestinal epithelial homeostasis by modulating cell proliferation, differentiation, and migration. Differentiation 99:51-61
Chumanevich, Anastasiya A; Chaparala, Anusha; Witalison, Erin E et al. (2017) Looking for the best anti-colitis medicine: A comparative analysis of current and prospective compounds. Oncotarget 8:228-237
Alexander, M; Burch, J B; Steck, S E et al. (2017) Case-control study of candidate gene methylation and adenomatous polyp formation. Int J Colorectal Dis 32:183-192
Zhang, Yu; Davis, Celestia; Shah, Sapana et al. (2017) IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis. Mol Carcinog 56:272-287
Gao, Feng J; Shi, Liang; Hines, Timothy et al. (2017) Insulin signaling regulates a functional interaction between adenomatous polyposis coli and cytoplasmic dynein. Mol Biol Cell 28:587-599
Gao, Song; Carson, James A (2016) Lewis lung carcinoma regulation of mechanical stretch-induced protein synthesis in cultured myotubes. Am J Physiol Cell Physiol 310:C66-79
Peña, Edsel A (2016) Asymptotics for a Class of Dynamic Recurrent Event Models. J Nonparametr Stat 28:716-735
Kindo, Bereket P; Wang, Hao; Peña, Edsel A (2016) Multinomial probit Bayesian additive regression trees. Stat (Int Stat Inst) 5:119-131
Carson, James A; Hardee, Justin P; VanderVeen, Brandon N (2016) The emerging role of skeletal muscle oxidative metabolism as a biological target and cellular regulator of cancer-induced muscle wasting. Semin Cell Dev Biol 54:53-67

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