Mitogen-activated protein kinases potentiate thyroid hormone receptor transcriptional activity by stabilizing its protein.
Transcriptional regulation of downstream gene expression by thyroid hormone (T(3)) is mediated by the thyroid hormone receptor (TR). T(3) binding induces a complicated transition, where TR converts from a transcriptional repressor into a transcriptional activator and instigates downstream gene transcription. Binding of T(3) to TR also induces the degradation of TR, resulting in desensitization of the cells to further T(3) treatment. It has been shown that phosphorylation of TR plays a critical role in its activity and stability after T(3) 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.
Chen
Shen Liang
SL
Department of Biochemistry, Chang Gung University School of Medicine, Kweisan Taoyuan 333, Taiwan, Republic of China.
Chang
Yu Jung
YJ
Wu
Yi Hsin
YH
Lin
Kwang Huei
KH
D000818:Animals; D004247:DNA / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051958:Nuclear Receptor Coactivator 2; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000502:physiology; D017434:Protein Structure, Tertiary; D020218:Response Elements / Q000502:physiology; D037042:Thyroid Hormone Receptors beta / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D008024:Ligands; D051958:Nuclear Receptor Coactivator 2; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors; D014284:Triiodothyronine; D004247:DNA; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases