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• W2058787887 abstract "PTEN is a major tumor suppressor gene inactivated in over 30% of human cancer. It encodes a lipid phosphatase with specificity towards phosphatidylinositol (3,4,5) triphosphate (PIP3). PTEN phosphatase activity is crucial to its ability to control cell size, proliferation, motility and survival. The role of PTEN in human breast cancer is well-established. Although the frequency of PTEN mutation in human breast cancer is low (5-10%), a significant fraction of advanced breast cancer has reduced PTEN expression. Furthermore, germ line mutation in PTEN gene constitutes the genetic basis of Cowden9s Disease (CD) Syndrome. CD is a harmatoma syndrome with patients displaying aberrant overgrowth of multiple tissue types. Individuals are at a greater risk of developing malignancy of the breast, colon, skin and thyroid. Our laboratory has identified a unique mutation in the C2 loop of PTEN from a human metastatic breast carcinoma cell line, MDA-MB-453. A G to A change substitutes the glutamate (GAG) at codon 307 (E307) to a lysine (AAA). The PTEN C2 loop (aa282-312) is a region on the cytosolic side of the C2 membrane-binding domain. Mono-ubiquitination at K289 within the C2 loop has been shown to promote nuclear translocation. More importantly, unlike the wild-type protein, the E307K mutant is almost undetectable in the nuclear compartment of MDA-MB-453. Biochemically, PTEN E307K mutant displayed similar phosphatase activity towards soluble lipid substrates. More importantly, PTEN E307K displays a striking ability to form an affinity complex with the p53 tumor suppressor. Consistent with this finding, the expression of E307K exerts chemoprotective effect against cisplatinum induced cell death. Based on this preliminary data, we hypothesize that the negatively-charged glutamate residues of PTEN C2 loop play regulatory roles in nuclear translocation and p53-binding. Mutating those residues to lysine creates cryptic ubiquitination sites that subvert the natural ubiquitination at K289, and thus impedes nuclear translocation. Funding: DOD - DAMD17-03-1-0682 (AMC); NCI - RO1CA095063 (AMC), T32CA078207 (GS); Midwest Athletes against Childhood Cancer (AMC); Advancing Healthy Wisconsin Funds (AMC) Acknowledgement: Dr. Xuejun Jiang (Memorial Sloan Kettering Cancer Center, NY) and Dr. Zhen-Qiang Pan (Mount Sinai School of Medicine, NY) for providing the NEDD4-1 and ubiquitination reagents Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1124." @default.
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• W2058787887 date "2010-04-15" @default.
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• W2058787887 title "Abstract 1124: Characterization of a PTEN C2 loop mutation in a human breast cancer cell line" @default.
• W2058787887 doi "https://doi.org/10.1158/1538-7445.am10-1124" @default.
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