Thyroid hormone receptor mutations found in renal clear cell carcinomas alter corepressor release and reveal helix 12 as key determinant of corepressor specificity.
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 T(3), 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 T(3).
Rosen
Meghan D
MD
Department of Microbiology, University of California at Davis, Davis, California 95616, USA.
Privalsky
Martin L
ML
D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D006728:Hormones / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D012097:Repressor Proteins / Q000378:metabolism; D015533:Transcriptional Activation
D006728:Hormones; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins