Thyroid hormone, operating through its receptors, plays crucial roles in the control of normal human physiology and development; deviations from the norm can give rise to disease. Clinical endocrinologists often must confront and correct the consequences of inappropriately high or low thyroid hormone synthesis. Although more rare, disruptions in thyroid hormone endocrinology due to aberrations in the receptor also have severe medical consequences. This review will focus on the afflictions that are caused by, or are closely associated with, mutated thyroid hormone receptors. These include Resistance to Thyroid Hormone Syndrome, erythroleukemia, hepatocellular carcinoma, renal clear cell carcinoma, and thyroid cancer. We will describe current views on the molecular bases of these diseases, and what distinguishes the neoplastic from the non-neoplastic. We will also touch on studies that implicate alterations in receptor expression, and thyroid hormone levels, in certain oncogenic processes.
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).
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