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COUP-TFII acts downstream of Wnt/beta-catenin signal to silence PPARgamma gene expression and repress adipogenesis.

ABSTRACT: Wnt signaling through beta-catenin and TCF maintains preadipocytes in an un-differentiated proliferative state; however, the molecular pathway has not been completely defined. By integrating gene expression microarray, chromatin immunoprecipitation-chip, and cell-based experimental approaches, we show that Wnt/beta-catenin signaling activates the expression of COUP-TFII which recruits the SMRT corepressor complex to the first introns located downstream from the first exons of both PPARgamma1 and gamma2 mRNAs. This maintains the local chromatin in a hypoacetylated state and represses PPARgamma gene expression to inhibit adipogenesis. Our experiments define the COUP-TFII/SMRT complex as a previously unappreciated component of the linear pathway that directly links Wnt/beta-catenin signaling to repression of PPARgamma gene expression and the inhibition of adipogenesis.

SUBMITTER: Okamura M

PROVIDER: S-EPMC2667001 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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COUP-TFII acts downstream of Wnt/beta-catenin signal to silence PPARgamma gene expression and repress adipogenesis.

Okamura Masashi M Kudo Hiromi H Wakabayashi Ken-ichi K Tanaka Toshiya T Nonaka Aya A Uchida Aoi A Tsutsumi Shuichi S Sakakibara Iori I Naito Makoto M Osborne Timothy F TF Hamakubo Takao T Ito Sadayoshi S Aburatani Hiroyuki H Yanagisawa Masashi M Kodama Tatsuhiko T Sakai Juro J

Proceedings of the National Academy of Sciences of the United States of America 20090323 14

Wnt signaling through beta-catenin and TCF maintains preadipocytes in an un-differentiated proliferative state; however, the molecular pathway has not been completely defined. By integrating gene expression microarray, chromatin immunoprecipitation-chip, and cell-based experimental approaches, we show that Wnt/beta-catenin signaling activates the expression of COUP-TFII which recruits the SMRT corepressor complex to the first introns located downstream from the first exons of both PPARgamma1 and ...[more]

PMID: 19307559

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Project description:BACKGROUND:Aberrant Wnt/?-catenin signaling is associated with breast cancer even though genetic mutations in Wnt signaling components are rare. We have previously demonstrated that Rad6B, an ubiquitin conjugating enzyme, stabilizes ?-catenin via polyubiqutin modifications that render ?-catenin insensitive to proteasomal degradation. Rad6B is a transcriptional target of ?-catenin, creating a positive feedback loop between Rad6B expression and ?-catenin activation. METHODS:To isolate subpopulations expressing high or low Rad6B levels, we transfected MDA-MB-231 or WS-15 human breast cancer cells with ZsGreen fluorescent reporter vector in which the expression of ZsGreen was placed under the control of Rad6B promoter. ZsGreenhigh and ZsGreenlow subpopulations, reflective of high and low Rad6B promoter activity, respectively, were isolated by FACS. To determine the relevance of Wnt signaling in Rad6B-mediated ?-catenin stabilization/activation, the ZsGreenhigh cells were transfected with signaling-defective Wnt coreceptor LRP6?173. Rad6B expression and promoter activity were determined by RT-PCR, Western blot and Rad6B promoter-mediated luciferase assays. ?-catenin levels and transcriptional activity were determined by Western blot and TOP/FOP Flash reporter assays. Tumor formation and morphologies of ZsGreenlow, ZsGreenhigh, and ZsGreenhigh/LRP6?173 cells compared to unsorted vector controls were evaluated in nude mice. Expression of Wnt signaling related genes was profiled using the Wnt signaling pathway RT2 Profiler PCR arrays. RESULTS:ZsGreenhigh subpopulations showed high Rad6B expression and Rad6B promoter activity as compared to ZsGreenlow cells. ZsGreenhigh (high Rad6B expressors) also showed elevated ?-catenin levels and TOP/Flash activity. Inhibiting Wnt signaling in the high Rad6B expressors decreased ZsGreen fluorescence, Rad6B gene expression, ?-catenin levels and TOP/Flash activity. Tumors derived from high Rad6B expressors were predominantly composed of cells with epithelial mesenchymal transition (EMT) phenotype as compared to control tumors that were composed of both cuboidal and EMT-type cells. Tumors derived from low Rad6B expressors lacked EMT phenotype. Inhibition of LRP6 function in the high Rad6B expressors abrogated the EMT phenotype. Gene expression profiling showed upregulation of several Wnt signaling pathway regulators in high Rad6B expressors that were downregulated by interference of Wnt signaling with mutant LRP6 or by Rad6B silencing. CONCLUSIONS:These data reveal a functional link between the canonical Wnt pathway and Rad6B in ?-catenin activation and breast cancer progression.

Dataset Information

COUP-TFII acts downstream of Wnt/beta-catenin signal to silence PPARgamma gene expression and repress adipogenesis.

Publications

COUP-TFII acts downstream of Wnt/beta-catenin signal to silence PPARgamma gene expression and repress adipogenesis.

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