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KMID : 1202020080010010048
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Journal of Korean Thyroid Association
2008 Volume.1 No. 1 p.48 ~ p.59
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Regulation of Translation Initiation by Thyrotropin and the Antithyroid Drug, Methimazole, in Thyroid Cells
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Song Jung-Hun
Shong Min-Ho
Ro Heung-Kyu
Jo Young-Suk
Park Ki-Cheol
Kweon Gi-Ryang
Kim Soung-Jung
Lee Min-Hee
Hwang Jung-Hwan
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Abstract
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Background and Objectives: Unlike proliferation, the signaling pathways of translation mechanism by TSH are not well defined. Therefore, we investigate the role of TSH and methimazole (MMI), an antithyroid drug, in the translational control of protein synthesis in thyrocytes.
Materials and Methods: Expression and phosphorylation of translation regulatory proteins were determined by Western blot analysis and eukaryotic translation initiation factor 4E (eIF4E) bound eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) was measured by immunoblot analysis and 7-methyl-GTP-sepharose-binding assay. Protein synthesis was monitored by incorporation of [35S]methionine and AMP-activated protein kinase (AMPK) activity was measured by in vitro kinase assay.
Results: TSH regulates phosphorylation of downstream effectors of phosphatidylinositol 3 kinase (PI3K) signaling, such as Akt, 4E-BP1, and ribosomal protein S6 (rpS6). TSH-dependent 4E-BP1 phosphorylation and its subsequent dissociation from eIF4E resulted in activation of cap-dependent translation initiation. TSH-mediated activation of cap-dependent protein biosynthesis occurred through TSH receptor- (TSHR-), PI3K- and mTOR-dependent signaling pathways. Methimazole increased AMPK activity in FRTL-5 cells. Activation of AMPK resulted in down-regulation of mTOR-dependent translation initiation mediated by phosphorylated 4E-BP1 and rpS6.
Conclusion: TSH regulates cap-dependent translation initiation through PI3K- and mTOR-dependent pathways. MMI inhibits these effects of TSH through activation of AMPK and inhibition of mTOR.
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KEYWORD
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Translation, Thyrotropin, Methimazole, Phosphatidylinositol 3 kinase, AMP-activated protein kinase
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