DOI: 10.1073/pnas.160257997. Hormone binding induces rapid proteasome-mediated degradation of thyroid hormone receptors

Hormone binding induces rapid proteasome-mediated degradation of thyroid hormone receptors

10.1073/pnas.160257997

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

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 TRβ1 was ubiquitinated and that the ubiquitination was T3 independent. Studies with a series of truncated TRβ1 showed that the hormone-binding domain was sufficient for the T3-induced rapid degradation of TRβ1 by the proteasome degradation pathway. T3 also induced rapid degradation of TRβ2 and TRα1. In contrast, the stability of the non-T3-binding TRα2 and naturally occurring TRβ1 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 TRβ1 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.

Bibliography

Dace, A., Zhao, L., Park, K. S., Furuno, T., Takamura, N., Nakanishi, M., West, B. L., Hanover, J. A., & Cheng, S. (2000). Hormone binding induces rapid proteasome-mediated degradation of thyroid hormone receptors. Proceedings of the National Academy of Sciences, 97(16), 8985â8990.

Authors 9

Alexandra Dace (first)
Li Zhao (additional)
Kyung Soo Park (additional)
T. Furuno (additional)
N. Takamura (additional)
M. Nakanishi (additional)
Brian L. West (additional)
John A. Hanover (additional)
Sheue-yann Cheng (additional)

References 29 Referenced 118

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Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:41 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 12:46 a.m.)
Indexed	2 months, 1 week ago (June 25, 2025, 7:27 p.m.)
Issued	25 years, 1 month ago (July 25, 2000)
Published	25 years, 1 month ago (July 25, 2000)
Published Online	25 years, 1 month ago (July 25, 2000)
Published Print	25 years, 1 month ago (Aug. 1, 2000)

Funders 0

None

BibTeX

@article{Dace_2000, title={Hormone binding induces rapid proteasome-mediated degradation of thyroid hormone receptors}, volume={97}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.160257997}, DOI={10.1073/pnas.160257997}, number={16}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Dace, Alexandra and Zhao, Li and Park, Kyung Soo and Furuno, T. and Takamura, N. and Nakanishi, M. and West, Brian L. and Hanover, John A. and Cheng, Sheue-yann}, year={2000}, month=jul, pages={8985–8990} }

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  "abstract": "<jats:p>\n            The thyroid hormone 3,3\u2032,5-triiodo-\n            <jats:sc>l</jats:sc>\n            -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\u2013proteasome degradation pathway. Immunoblots demonstrated that the transfected TR\u03b21 was ubiquitinated and that the ubiquitination was T3 independent. Studies with a series of truncated TR\u03b21 showed that the hormone-binding domain was sufficient for the T3-induced rapid degradation of TR\u03b21 by the proteasome degradation pathway. T3 also induced rapid degradation of TR\u03b22 and TR\u03b11. In contrast, the stability of the non-T3-binding TR\u03b12 and naturally occurring TR\u03b21 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\u03b21 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\u2013proteasome degradation pathway.\n          </jats:p>",
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