This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, S. L. Articles by Lin, K. H. Search for Related Content PubMed PubMed Citation Articles by Chen, S. L. Articles by Lin, K. H. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB LIOTHYRONINE

Mitogen-Activated Protein Kinases Potentiate Thyroid Hormone Receptor Transcriptional Activity by Stabilizing Its Protein

Department of Biochemistry, Chang Gung University School of Medicine, Kweisan Taoyuan 333, Taiwan, Republic of China

Address all correspondence and requests for reprints to: Kwang Huei Lin, Ph.D., Department of Biochemistry, Chang Gung University School of Medicine, 259 Wen-hwa First Road, Kweisan Taoyuan 333, Taiwan, Republic of China. E-mail: khlin{at}mail.cgu.edu.tw.

Transcriptional regulation of downstream gene expression by thyroid hormone (T₃) is mediated by the thyroid hormone receptor (TR). T₃ binding induces a complicated transition, where TR converts from a transcriptional repressor into a transcriptional activator and instigates downstream gene transcription. Binding of T₃ to TR also induces the degradation of TR, resulting in desensitization of the cells to further T₃ treatment. It has been shown that phosphorylation of TR plays a critical role in its activity and stability after T₃ binding. However, the kinases in control of phosphorylating TR in the nucleus have not been identified. In this study we demonstrate that MAPKs are possible candidates responsible for the nuclear phosphorylation of TR. Suppression of MAPKs with specific inhibitors repressed TR transcriptional activity and antagonized okadeic acid-induced TR transcriptional activity potentiation. Overexpression of the MAPK activator, MKK6, and its constitutively active mutant, MKK6EE, significantly increased TR activity and protected TR from degradation. Involvement of the 26S ubiquitin proteasome in hormone binding-induced TR degradation was also examined. We found that MAPKs enhanced the DNA binding affinity of TR. Our results suggest that MAPKs are the major kinases responsible for the nuclear phosphorylation of TR and are critical factors modulating the transcriptional activity and protein stability of TR subsequent to ligand binding.

This article has been cited by other articles:

				M. R. Bratton, D. E. Frigo, K. A. Vigh-Conrad, D. Fan, S. Wadsworth, J. A. McLachlan, and M. E. Burow Organochlorine-mediated potentiation of the general coactivator p300 through p38 mitogen-activated protein kinase Carcinogenesis, January 1, 2009; 30(1): 106 - 113. [Abstract] [Full Text] [PDF]

				R. Narayanan, C. C. Coss, M. Yepuru, J. D. Kearbey, D. D. Miller, and J. T. Dalton Steroidal Androgens and Nonsteroidal, Tissue-Selective Androgen Receptor Modulator, S-22, Regulate Androgen Receptor Function through Distinct Genomic and Nongenomic Signaling Pathways Mol. Endocrinol., November 1, 2008; 22(11): 2448 - 2465. [Abstract] [Full Text] [PDF]

				R.-N. Chen, Y.-H. Huang, Y.-C. Lin, C.-T. Yeh, Y. Liang, S.-L. Chen, and K.-H. Lin Thyroid Hormone Promotes Cell Invasion through Activation of Furin Expression in Human Hepatoma Cell Lines Endocrinology, August 1, 2008; 149(8): 3817 - 3831. [Abstract] [Full Text] [PDF]

				J. Lei, C. N. Mariash, M. Bhargava, E. V. Wattenberg, and D. H. Ingbar T3 increases Na-K-ATPase activity via a MAPK/ERK1/2-dependent pathway in rat adult alveolar epithelial cells Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L749 - L754. [Abstract] [Full Text] [PDF]

				I. Irrcher, D. R. Walkinshaw, T. E. Sheehan, and D. A. Hood Thyroid hormone (T3) rapidly activates p38 and AMPK in skeletal muscle in vivo J Appl Physiol, January 1, 2008; 104(1): 178 - 185. [Abstract] [Full Text] [PDF]

				P.-J. Tai, Y.-H. Huang, C.-H. Shih, R.-N. Chen, C.-D. Chen, W.-J. Chen, C.-S. Wang, and K.-H. Lin Direct Regulation of Androgen Receptor-Associated Protein 70 by Thyroid Hormone and Its Receptors Endocrinology, July 1, 2007; 148(7): 3485 - 3495. [Abstract] [Full Text] [PDF]

				D. E. Frigo, A. Basu, E. N. Nierth-Simpson, C. B. Weldon, C. M. Dugan, S. Elliott, B. M. Collins-Burow, V. A. Salvo, Y. Zhu, L. I. Melnik, et al. p38 Mitogen-Activated Protein Kinase Stimulates Estrogen-Mediated Transcription and Proliferation through the Phosphorylation and Potentiation of the p160 Coactivator Glucocorticoid Receptor-Interacting Protein 1 Mol. Endocrinol., May 1, 2006; 20(5): 971 - 983. [Abstract] [Full Text] [PDF]

				M.-B. Poirier, G. Hamann, M.-E. Domingue, M. Roy, T. Bardati, and M.-F. Langlois General Receptor for Phosphoinositides 1, a Novel Repressor of Thyroid Hormone Receptor Action that Prevents Deoxyribonucleic Acid Binding Mol. Endocrinol., August 1, 2005; 19(8): 1991 - 2005. [Abstract] [Full Text] [PDF]

				P. Maruvada, N. I. Dmitrieva, J. East-Palmer, and P. M. Yen Cell Cycle-dependent Expression of Thyroid Hormone Receptor-{beta} Is a Mechanism for Variable Hormone Sensitivity Mol. Biol. Cell, April 1, 2004; 15(4): 1895 - 1903. [Abstract] [Full Text] [PDF]