Thyroid hormone receptor beta mutants: Dominant negative regulators of peroxisome proliferator-activated receptor gamma action.
Thyroid hormone (T3) and peroxisome proliferators have overlapping metabolic effects in the maintenance of lipid homeostasis. Their actions are mediated by their respective receptors: thyroid hormone receptors (TR) and peroxisome proliferator-activated receptors (PPAR). We recently found that a dominantly negative TRbeta mutant (PV) that causes a genetic disease, resistance to thyroid hormone, acts to repress the ligand (troglitazone)-mediated transcriptional activity of PPARgamma in cultured thyroid cells. This finding suggests that TRbeta mutants could crosstalk with PPARgamma-signaling pathways. The present study explored the molecular mechanisms by which PV represses the PPARgamma transcriptional activity. Gel-shift assays show that the PV, similar to wild-type TRbeta, bound to the peroxisome proliferator response element (PPRE) as homodimers and heterodimers with PPARgamma or the retinoid X receptor (RXR), thereby competing with PPARgamma for binding to PPRE and for sequestering RXR. Association of PPRE-bound PV with corepressors [e.g., nuclear receptor corepressor (NCoR)] that led to transcriptional repression was independent of T3 and troglitazone. Chromatin immunoprecipitation assay further demonstrated that, despite the presence of ligands, NCoR was recruited to PPRE-bound PV on a PPARgamma-target gene, the lipoprotein lipase, in vivo, suggesting the dominant action of PV on PPARgamma-mediated transcriptional activity. Thus, the dominant negative action of PV is not limited on the wild-type TRs. The findings that TRbeta mutants affect PPARgamma functions through dominant negative action provide insights into the molecular mechanisms by which TR regulates the PPARgamma-target genes involved in metabolic pathways, lipid homeostasis, and carcinogenesis.
Araki
Osamu
O
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA.
Ying
Hao
H
Furuya
Fumihiko
F
Zhu
Xuguang
X
Cheng
Sheue-Yann
SY
D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D019281:Dimerization; D051548:Histone Acetyltransferases; D051379:Mice; D009154:Mutation; D056920:Nuclear Receptor Coactivator 1; D047495:PPAR gamma / Q000737:chemistry / Q000502:physiology*; D011401:Promoter Regions, Genetic; D020218:Response Elements; D047488:Retinoid X Receptors / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D015533:Transcriptional Activation; D000077288:Troglitazone
D002839:Chromans; D047495:PPAR gamma; D047488:Retinoid X Receptors; D045162:Thiazolidinediones; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1; D000077288:Troglitazone