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The role of PTEN in human cancer

Indiana University-Purdue University Indianapolis (IUPUI) / Phosphatase and tensin homolog, PTEN, is a key tumor suppressor. Mutation of PTEN is associated with both sporadic cancers and a cluster of familial cancer predisposition syndromes called PTEN hamaratoma syndromes. These germline mutations span the length of the PTEN gene with a mutational hot spot localized in exon 5. This exon encodes the catalytic domain of PTEN, which is critical for its tumor suppressor activity. PTEN function is most commonly attributed to lipid phosphatase activity on Phosphatidylinositol (3,4,5)-trisphosphate (PIP3) that leads to inhibition of a cascade with downstream pro-survival effectors including Akt, but PTEN also has phosphatase activity on a small number of proteins. Recently, a mutation, G129E, has been described as a gain of function (GOF) mutation in PTEN knockin mice. This mutant only retains protein phosphatase activity while it completely lacks lipid phosphatase activity. Collectively (in the mouse and in vitro studies), there is no clear mechanism to explain the GOF nature of this mutant. Understanding how mutants of PTEN function in the cells to provide a growth advantage will provide insight into what pathway to therapeutically target. Our central hypothesis is that mutations of PTEN promote tumorigenesis through gain of function activities that result in cell cycle progression. We will determine the signaling pathways that are affected by the gain of function mutant PTEN G129E to better understand the mechanism by which mutants of PTEN confer a growth advantage.

Identiferoai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/7934
Date January 2015
CreatorsGendron, Jaimie Michelle
ContributorsMayo, Lindsey D., Goebl, Mark G., Harrington, Maureen A., Naidu, Samisubbu
Source SetsIndiana University-Purdue University Indianapolis
Languageen_US
Detected LanguageEnglish
TypeThesis
RightsCC0 1.0 Universal, http://creativecommons.org/publicdomain/zero/1.0/

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