Molecular mechanisms of Kruppel-like Factor 4

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Title: Molecular mechanisms of Kruppel-like Factor 4
Author: Paul Michael Evans
Abstract: The Wnt /beta -catenin pathway is a key pathway involved in the regulation of proliferation and differentiation within many tissues , including the epithelium of the intestine and of the skin . Wnt signaling is implicated in stem cell renewal . Deregulation of Wnt /beta -catenin signaling is crucial early event in colorectal tumorigenesis . Earlier work in our lab demonstrated that Kruppel -like factor 4 (KLF4 ) interacts with beta -catenin in vivo , repressing Wnt signaling and inhibiting tumor growth . KLF4 is an anti -proliferative transcription factor expressed in differentiated epithelial cells in the intestine . Previous studies clearly establish KLF4 as a tumor suppressor in colorectal cancer . Expression of KLF4 is downregulated in colorectal tumors , and heterozygous deletion of the Klf4 allele in a mouse model of colorectal cancer results in the formation of approximately 50 % more tumors . In addition , KLF4 is important in stem cell programming . KLF4 , in combination with three additional transcription factors , is sufficient to reprogram differentiated fibroblasts into embryonic stem cells . This dissertation focuses on the molecular mechanisms of KLF4 -mediated transcription , both in the context of KLF4 -mediated activation and KLF4 -mediated repression . I demonstrate that the N -terminal transactivation domain of KLF4 recruits the co -activator p300 /CBP to the promoter of the positively -regulated gene IAP , resulting in increased histone acetylation . On the negatively regulated gene , Cyclin B1 , I demonstrate that KLF4 recruits HDAC3 , decreasing histone acetylation . In addition , I show that KLF4 is acetylated by p300 /CBP , and that acetylation of KLF is important in the activation of target genes as well as its ability to inhibit proliferation . I demonstrate that KLF4 inhibits Wnt -catenin signaling by blocking beta -catenin -mediated recruitment of p300 /CBP to Wnt -regulated genes . Finally , I show that acetylation of beta -catenin is important in its ability to interact with p300 /CBP and that KLF4 inhibits beta -catenin acetylation . These studies provide significant insight into the molecular mechanisms of KLF4 -mediated transcription , and will prove useful in the development of targeted therapies for colorectal cancer as well as providing a deeper understanding of the mechanisms behind stem cell reprogramming .
URI: http : / /hdl .handle .net /2152 .3 /231
Date: 2008-06-18

Citation

Molecular mechanisms of Kruppel-like Factor 4. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /231 .

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