All ETDs from UAB

Advisory Committee Chair

Fang-Tsyr Lin

Advisory Committee Members

Susan L Bellis

Etty N Benveniste

Danny R Welch

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

TRIP6 is a focal adhesion molecule that functions as an adaptor protein to mediate diverse cellular functions, including motility and antiapoptotic signaling, through a wide variety of protein-protein interactions. We were able to characterize a novel interaction between TRIP6 and p27KIP1, a CDK inhibitor which can both suppress and promote tumorigenesis, depending on its regulation. TRIP6 expression specifically promotes the AKT-mediated phosphorylation of p27KIP1 at T157, which leads to its cytosolic retention, and accelerates the protein turnover rate of p27KIP1. We also found that phosphorylation of T157 by itself promotes cell motility and can be linked to the formation of motility-associated cytoskeletal structures, including podosome-like actin bundles. Finally, we were able to demonstrate that TRIP6 knockdown inhibits tumorigenesis of both ovarian cancer and glioblastoma xenografts in vivo and that its overexpression correlates to poor outcome in human gliomas. Because of these findings, TRIP6 may be useful as a novel prognostic biomarker for the assessment of all human gliomas, as well as a target for future therapeutic interventions.

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