Nuclear corepressors enhance the dominant negative activity of mutant receptors that cause resistance to thyroid hormone

Endocrinology
T Tagami, J L Jameson

Abstract

The syndrome of resistance to thyroid hormone (RTH) is caused by multiple distinct mutations in the ligand-binding domain of the thyroid hormone receptor-beta (TRbeta). Although the mutant receptors are transcriptionally inactive, they inhibit normal receptor function in a dominant negative manner to cause hormone resistance. Recently, a group of transcriptional cofactors, referred to as corepressors (CoRs), was shown to induce ligand-independent silencing of genes that contain positive T3 response elements. CoRs also play a role in the ligand-independent basal activation of genes that are negatively regulated in response to T3. We hypothesized that CoR might play a role in the dominant negative inhibition by TRbeta mutants that cause RTH. In gel mobility shift assays, RTH mutants retained interactions with CoRs even in the presence of T3, whereas the ligand dissociated CoR from wild-type TRbeta. Using Gal4-TR chimeric receptors and a VP16-CoR fusion protein in an interaction assay, a strong positive correlation was found between mutant receptor interactions with CoR and transcriptional silencing activity. A mutation (P214R) that impairs CoR interactions with TR was introduced into the RTH mutants to assess the role of CoR in d...Continue Reading

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Citations

Nov 2, 2005·Proceedings of the National Academy of Sciences of the United States of America·Osamu ArakiSheue-Yann Cheng
Dec 5, 2008·Proceedings of the National Academy of Sciences of the United States of America·Inna AstapovaAnthony N Hollenberg
May 15, 2009·Proceedings of the National Academy of Sciences of the United States of America·Danielle S MachadoFredric E Wondisford
Jan 23, 1999·The Journal of Clinical Investigation·E D AbelF E Wondisford
Jan 7, 2010·Endocrine Reviews·Sheue-Yann ChengPaul J Davis
Feb 10, 2012·The Journal of Clinical Endocrinology and Metabolism·Alfonso Massimiliano FerraraSamuel Refetoff
Jul 16, 2011·Journal of Thyroid Research·Meghan D Rosen, Martin L Privalsky
Sep 22, 2018·Thyroid : Official Journal of the American Thyroid Association·Déborah HarrusAlbane le Maire
Aug 1, 2015·The American Journal of Chinese Medicine·Juan-E LiKenji Moriyama
Oct 12, 2000·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·L J Burke, A Baniahmad
Aug 24, 1999·Molecular and Cellular Biology·J ZhangM A Lazar
Jun 28, 2001·Physiological Reviews·P M Yen
Sep 16, 1998·Thyroid : Official Journal of the American Thyroid Association·R J Koenig

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