Thyroid hormone receptor mutations found in renal clear cell carcinomas alter corepressor release and reveal helix 12 as key determinant of corepressor specificity

Meghan D. Rosen, Martin L. Privalsky

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Thyroid hormone receptors (TRs) regulate multiple normal physiological and developmental pathways, whereas mutations in TRs can result in endocrine and neoplastic disease. A particularly high rate of TR mutations has been found in human renal clear cell carcinomas (RCCCs). We report here that the majority of these RCCC TR mutants tested are defective for transcriptional activation and behave as dominant-negative inhibitors of wild-type receptor function. Although several of the dominant-negative RCCC TR mutants are impaired for hormone binding, all fail to release from corepressors appropriately in response to T3, a trait that closely correlates with their defective transcriptional properties. Notably, many of these mutants exhibit additional changes in their specificity for different corepressor splice forms that may further contribute to the disease phenotype. Mapping of the relevant mutations reveals that the C-terminal receptor helix 12 is not simply a hormone-operated switch that either permits or prevents all corepressor binding, but is instead a selective gatekeeper that actively discriminates between different forms of corepressor even in the absence of T3.

Original languageEnglish (US)
Pages (from-to)1183-1192
Number of pages10
JournalMolecular Endocrinology
Volume23
Issue number8
DOIs
StatePublished - Aug 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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