期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2000
卷号：97
期号：16
页码：8985-8990
DOI：10.1073/pnas.160257997
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The thyroid hormone 3,3',5-triiodo-L-thyronine (T3) is essential for growth, differentiation, and development. Its biological activities are mediated by T3 nuclear receptors (TRs). At present, how T3 regulates TR proteins and the resulting functional consequences are still unknown. Immunofluorescence analyses of endogenous TR in the growth hormone-producing GC cells showed that the T3-induced rapid degradation of TR was specifically blocked by lactacystin, a selective inhibitor of the ubiquitin-proteasome degradation pathway. Immunoblots demonstrated that the transfected TR{beta}1 was ubiquitinated and that the ubiquitination was T3 independent. Studies with a series of truncated TR{beta}1 showed that the hormone-binding domain was sufficient for the T3-induced rapid degradation of TR{beta}1 by the proteasome degradation pathway. T3 also induced rapid degradation of TR{beta}2 and TR1. In contrast, the stability of the non-T3-binding TR2 and naturally occurring TR{beta}1 mutants that do not bind T3 was not affected by T3 treatment, indicating that hormone binding to receptor was essential for the degradation of the wild-type receptors. In the presence of proteasome protease inhibitors, the levels of both total and ubiquitinated TR{beta}1 protein increased, yet T3-dependent transcriptional activation and the expression of the growth hormone gene were diminished, suggesting that proteasome-mediated degradation played a novel role in modulating transcriptional activation by TR. The present study reveals a role of T3 in modulating the functions of TR by regulating its receptor level via the ubiquitin-proteasome degradation pathway.
