PMID- 16717100 OWN - NLM STAT- MEDLINE DCOM- 20060918 LR - 20211203 IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 281 IP - 30 DP - 2006 Jul 28 TI - Thyroid hormone stimulates protein synthesis in the cardiomyocyte by activating the Akt-mTOR and p70S6K pathways. PG - 20666-20672 LID - S0021-9258(18)95195-1 [pii] LID - 10.1074/jbc.M512671200 [doi] AB - Thyroid hormones affect cardiac growth and phenotype; however, the mechanisms by which the hormones induce cardiomyocyte hypertrophy remain uncharacterized. Tri-iodo-L-thyronine (T3) treatment of cultured cardiomyocytes for 24 h resulted in a 41 +/- 5% (p < 0.001) increase in [(3)H]leucine incorporation into total cellular protein. This response was abrogated by the phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin. Co-immunoprecipitation studies showed a direct interaction of cytosol-localized thyroid hormone receptor TRalpha1 and the p85alpha subunit of PI3K. T3 treatment rapidly increased PI3K activity by 52 +/- 3% (p < 0.005), which resulted in increased phosphorylation of downstream kinases Akt and mammalian target of rapamycin (mTOR). This effect was abrogated by pretreatment with wortmannin or LY294002. Phosphorylation of p70(S6K), a known target of mTOR, occurred rapidly following T3 treatment and was inhibited by rapamycin and wortmannin. In contrast, phosphorylation of the p85 variant of S6K in response to T3 was not blocked by LY294002, wortmannin, or rapamycin, thus supporting a T3-activated pathway independent of PI3K and mTOR. 40 S ribosomal protein S6, a target of p70(S6K), and 4E-BP1, a target of mTOR, were both phosphorylated within 15-25 min of T3 treatment and could be inhibited by wortmannin and rapamycin. Thus, rapid T3-mediated activation of PI3K by cytosolic TRalpha1 and subsequent activation of the Akt-mTOR-S6K signaling pathway may underlie one of the mechanisms by which thyroid hormone regulates physiological cardiac growth. FAU - Kenessey, Agnes AU - Kenessey A AD - The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030. FAU - Ojamaa, Kaie AU - Ojamaa K AD - The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030; Departments of Cell Biology and Medicine, New York University School of Medicine, New York, New York 10016. Electronic address: kojamaa@nshs.edu. LA - eng GR - HL-071623/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20060522 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Chromones) RN - 0 (Enzyme Inhibitors) RN - 0 (Morpholines) RN - 06LU7C9H1V (Triiodothyronine) RN - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Cells, Cultured MH - Chromones/pharmacology MH - Cytosol/metabolism MH - Enzyme Activation MH - Enzyme Inhibitors/pharmacology MH - Morpholines/pharmacology MH - Myocytes, Cardiac/*metabolism MH - Phosphorylation MH - Protein Kinases/*metabolism MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Rats MH - Ribosomal Protein S6 Kinases, 70-kDa/*metabolism MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases MH - Triiodothyronine/metabolism/*physiology EDAT- 2006/05/24 09:00 MHDA- 2006/09/19 09:00 CRDT- 2006/05/24 09:00 PHST- 2006/05/24 09:00 [pubmed] PHST- 2006/09/19 09:00 [medline] PHST- 2006/05/24 09:00 [entrez] AID - S0021-9258(18)95195-1 [pii] AID - 10.1074/jbc.M512671200 [doi] PST - ppublish SO - J Biol Chem. 2006 Jul 28;281(30):20666-20672. doi: 10.1074/jbc.M512671200. Epub 2006 May 22.