Naturally Occurring Amino Acids in Helix 10 of the Thyroid Hormone Receptor Mediate Isoform-Specific TH Gene Regulation

Naturally Occurring Amino Acids in Helix 10 of the Thyroid Hormone Receptor Mediate Isoform-Specific TH Gene Regulation

Author Pinto, Vitor M. S. Autor UNIFESP Google Scholar
Minakhina, Svetlana Google Scholar
Qiu, Shuiqing Google Scholar
Sidhaye, Aniket Google Scholar
Brotherton, Michael P. Google Scholar
Suhotliv, Amy Google Scholar
Wondisford, Fredric E. Google Scholar
Abstract Thyroid hormone (TH) action is mediated by the products of two genes, TH receptor (THR) a (THRA) and THRb (THRB) that encode several closely related receptor isoforms with differing tissue distributions. The vast majority of THR isoform-specific effects are thought to be due to tissue-specific differences in THR isoform expression levels. We investigated the alternative hypothesis that intrinsic functional differences among THR isoforms mediate these tissue-specific effects. To achieve the same level of expression of each isoform, we created tagged THR isoforms and tested their DNA and functional properties in vitro. We found significant homodimerization and functional differences among the THR isoforms. THRA1 was unable to form homodimers on direct repeat separated by 4 bp DNA elements and was also defective in TH-dependent repression of Tshb and Rxrg in a thyrotroph cell line, T alpha T1.1. In contrast, THRB2 was both homodimer sufficient and fully functional on these negatively regulated genes. Using domain exchanges and individual amino acid switches between THRA1 and THRB2, we identified three amino acids in helix 10 of the THRB2 ligand-binding domain that are required for negative regulation and are absent in THRA1.
Language English
Sponsor National Institutes of Health (NIH)
Science Without Borders Program, CNPq
Grant number NIH: R01-DK49126
Date 2017
Published in Endocrinology. Cary, v. 158, n. 9, p. 3067-3078, 2017.
ISSN 0013-7227 (Sherpa/Romeo, impact factor)
Publisher Oxford Univ Press Inc
Extent 3067-3078
Origin http://dx.doi.org/10.1210/en.2017-00314
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000408840300031
URI http://repositorio.unifesp.br/handle/11600/51327

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