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Thyroid hormone receptor mutations found in renal clear cell carcinomas alter corepressor release and reveal helix 12
Meghan D Rosen1, Martin L Privalsky
1Department of Microbiology, University of California at Davis, Davis, California 95616, USA.
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 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).
Insights
Mutations in thyroid hormone receptors (TRs) are common in kidney cancer. Many TR mutants are defective in gene activation and inhibit normal TRs, potentially driving cancer development.
Area of Science:
- Endocrinology
- Molecular Biology
- Oncology
Background:
- Thyroid hormone receptors (TRs) are crucial regulators of physiological and developmental processes.
- Mutations in TRs are implicated in endocrine disorders and cancers, with a notable prevalence in renal clear cell carcinomas (RCCCs).
Purpose of the Study:
- To investigate the functional consequences of TR mutations found in RCCCs.
- To elucidate the molecular mechanisms by which these mutants contribute to disease pathogenesis.
Main Methods:
- Functional assays assessing transcriptional activation by TR mutants.
- Hormone binding studies and corepressor interaction analyses.
- Mutation mapping to identify key functional domains.
Main Results:
- The majority of RCCC TR mutants exhibit defective transcriptional activation.
- These mutants act as dominant-negative inhibitors of wild-type TR function.
- Mutants show impaired hormone binding and, critically, fail to release corepressors upon T(3) stimulation, correlating with their defective transcription.
- Altered specificity for corepressor splice forms was observed in many mutants.
- Mutations cluster in the C-terminal helix 12, revealing its role as a selective corepressor gatekeeper.
Conclusions:
- RCCC-associated TR mutations disrupt normal receptor function, leading to dominant-negative inhibition and altered corepressor interactions.
- The C-terminal helix 12 plays a critical role in discriminating between corepressors, even without hormone binding.
- These findings provide insights into the molecular basis of RCCC development and potential therapeutic strategies targeting TR signaling.
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