Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2008) 15 S22

Brigham and Women’s Hospital, Boston, Massachusetts, USA.


Thyroid hormone 3,5,3′-triiodothyronine (T3) and its precursor thyroxine (T4) are iodinated compounds known to influence gene expression in virtually every vertebrate tissue. Fundamentally, thyroid hormone signaling results from the interaction of nuclear thyroid hormone receptors (TRs) with specific target gene promoters, a process that can either enhance or repress transcription. This process is modulated via binding of thyroid hormone, the ligand, to the TRs, which results in alterations in the composition of the transcriptional complex. The modern paradigm of thyroid hormone action recognizes that thyroid hormone signaling in individual tissues can change even as serum hormone concentrations remain normal, thanks to local activation or inactivation of thyroid hormone. The underlying mechanism of these phenomena is deiodination. The iodothyronine deiodinases types I, II, and III (D1, D2, and D3, respectively) regulate the activity of thyroid hormone via removal of specific iodine moieties from the precursor molecule T4. D2 generates the active form of thyroid hormone T3 via deiodination of T4. In contrast, D3 inactivates T3 and, to a lesser extent, prevents T4 from being activated. Both T4 and T3 enter the cell via transporters, including the MCT8 and the OATP-C1. Once inside the cell, T4 can be activated via conversion to T3 by the D2 pathway, such that the cytoplasmic pool of T3 includes both T3 from the plasma and T3 generated by D2. Alternatively, D3 acts at the plasma membrane to decrease local T3 concentrations. Thus, the deiodinases are critical determinants of the cytoplasmic T3 pool and therefore modulate nuclear T3 concentration and TR saturation. Understanding the signaling pathways these enzymes are involved has developmental as well as therapeutic implications, given that both D2 and D3 can participate in the Hedgehog signaling cascades.

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