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TGF-beta Activated Kinase-1 (TAK1) Is a Critical Prostate Tumor Suppressor

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abstract
TGF-beta activated kinase-1 (TAK1) encoded by the MAP3K7 gene is a serine/threonine protein kinase that functions in the regulation of cell proliferation, apoptosis, differentiation and/or inflammation. Genetic studies have shown that hemizygous deletion of the MAP3K7 gene is frequent (32%) in prostate cancer patients and is significantly associated with high grade prostate tumor. We hypothesize that TAK1 is a critical prostate tumor suppressor. In vitro, we knocked down TAK1 in an established mouse prostatic progenitor/stem cell (PrP/SC) line (WFU3) and knocked out TAK1 in TAK1lox/lox mouse prostatic epithelial cells (MPECs). Deficiency of TAK1 promoted cell growth, migration and invasion in vitro. In addition, suppression of TAK1 attenuated the growth inhibitory effect of TGF-beta1, but did not affect TGF-beta1-induced cellular morphological changes and migration, suggesting that TAK1 may serve to convert TGF-beta1 from a tumor suppressor to a tumor promoter. In vivo, we used prostate tissue recombination models and prostate-specific TAK1 deletion animals to demonstrate that loss of TAK1 led to tumor formation, which directly supports our hypothesis. Moreover, we found that expression of E-cadherin was decreased in TAK1 knockdown PrP/SCs both in vivo and in vitro. More interestingly, TAK1 and E-cadherin expression were coordinately lost in high grade human prostate cancer, suggesting the important role for TAK1 in regulation of cell motility. Taken together, our data strongly support that loss of TAK1 promotes prostate tumorigenesis and TAK1 is a novel and critical prostate tumor suppressor.
subject
Prostate cancer
Prostate stem cells
TAK1
Tumor suppressor
contributor
Wu, Min (author)
Cramer, Scott D. (committee chair)
Shelness, Gregory S. (committee member)
Torti, Suzy V. (committee member)
Seals, Darren F. (committee member)
Sui, Guangchao (committee member)
date
2011-07-14T20:35:33Z (accessioned)
2011 (issued)
degree
Molecular Genetics & Genomics (discipline)
identifier
http://hdl.handle.net/10339/33452 (uri)
language
en (iso)
publisher
Wake Forest University
title
TGF-beta Activated Kinase-1 (TAK1) Is a Critical Prostate Tumor Suppressor
type
Dissertation

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