help button home button Endocrine Society Molecular Endocrinology ENDO 08 Sessions Library
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
This version published online on September 23, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0093
Molecular Endocrinology Vol. 0, No. 2004 200400931-
doi:10.1210/me.2004-0093
Copyright © 2004 by the Endocrine Society.
This Article
Right arrow Author Manuscript (PDF)
Right arrow All Versions of this Article:
19/1/102    most recent
Author Manuscript (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow NURSA Molecule Pages Link
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by CAO, X.
Right arrow Articles by SEO, H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by CAO, X.
Right arrow Articles by SEO, H.

Submitted on March 3, 2004
Accepted on September 14, 2004

Thyroid hormone induces rapid activation of Akt/PKB-mTOR-p70S6K cascade through PI3K in human fibroblasts

XIA CAO, FUKUSHI KAMBE, LARS C. MOELLER, SAMUEL REFETOFF, and HISAO SEO*

Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan (X.C., F.K. and H.S.) and Departments of Medicine (L.C.M. and S.R.), Pediatrics (S.R.) and Committee on Genetics (S.R.), The University of Chicago, Chicago, IL

* To whom correspondence should be addressed. E-mail: hseo{at}riem.nagoya-u.ac.jp.

We have demonstrated that 3,5,3'-triiodothyronine (T3) increases the expression of ZAKI-4{alpha}, an endogenous calcineurin inhibitor. In this study we characterized a T3-dependent signaling cascade leading to ZAKI-4{alpha} expression in human skin fibroblasts. We found that T3-dependent increase in ZAKI-4{alpha} was greatly attenuated by rapamycin, a specific inhibitor of a protein kinase, mammalian target of rapamycin (mTOR), suggesting the requirement of mTOR activation by T3. Indeed, T3 activated mTOR rapidly through S2448 phosphorylation, leading to the phosphorylation of p70S6K, a substrate of mTOR. This mTOR activation is mediated through PI3K-Akt/PKB signaling cascade because T3 induced Akt/PKB phosphorylation more rapidly than that of mTOR, and these T3-dependent phosphorylations were blocked by both PI3K inhibitors and by expression of a dominant negative PI3K ({Delta}p85{alpha}). Furthermore, the association between thyroid hormone receptor {beta}1 (TR{beta}1) and PI3K regulatory subunit p85{alpha}, and the inhibition of T3-induced PI3K activation and mTOR phosphorylation by a dominant negative TR (G345R) demonstrated the involvement of TR in this T3 action. The liganded TR induces the activation of PI3K and Akt/PKB, leading to the nuclear translocation of the later, which subsequently phosphorylates nuclear mTOR. The rapid activation of PI3K-Akt/PKB-mTOR-p70S6K cascade by T3 provides a new molecular mechanism for thyroid hormone action.
Key words: mTOR • ZAKI-4{alpha} • non-genomic • phosphorylation

NURSA Molecule Pages Link:

Nuclear Receptors:   TRβ
Ligands:   Thyroid hormone



This article has been cited by other articles:


Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
A. Radenne, M. Akpa, C. Martel, S. Sawadogo, D. Mauvoisin, and C. Mounier
Hepatic regulation of fatty acid synthase by insulin and T3: evidence for T3 genomic and nongenomic actions
Am J Physiol Endocrinol Metab, October 1, 2008; 295(4): E884 - E894.
[Abstract] [Full Text] [PDF]

Home page
 J Mol EndocrinolHome page
M. Pietrzak and M. Puzianowska-Kuznicka
Triiodothyronine utilizes phosphatidylinositol 3-kinase pathway to activate anti-apoptotic myeloid cell leukemia-1
J. Mol. Endocrinol., September 1, 2008; 41(3): 177 - 186.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
X. Lu, F. Kambe, X. Cao, Y. Kozaki, T. Kaji, T. Ishii, and H. Seo
3{beta}-Hydroxysteroid-{Delta}24 Reductase Is a Hydrogen Peroxide Scavenger, Protecting Cells from Oxidative Stress-Induced Apoptosis
Endocrinology, July 1, 2008; 149(7): 3267 - 3273.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
M. Yamauchi, F. Kambe, X. Cao, X. Lu, Y. Kozaki, Y. Oiso, and H. Seo
Thyroid Hormone Activates Adenosine 5'-Monophosphate-Activated Protein Kinase via Intracellular Calcium Mobilization and Activation of Calcium/Calmodulin-Dependent Protein Kinase Kinase-{beta}
Mol. Endocrinol., April 1, 2008; 22(4): 893 - 903.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
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]

Home page
 J ANIM SCIHome page
X. Yang, C. Yang, A. Farberman, T. C. Rideout, C. F. M. de Lange, J. France, and M. Z. Fan
The mammalian target of rapamycin-signaling pathway in regulating metabolism and growth
J Anim Sci, April 1, 2008; 86(14_suppl): E36 - E50.
[Abstract] [Full Text] [PDF]

Home page
 Annals of Clinical & Laboratory ScienceHome page
W. Feng, R. E. Brown, C. D. Trung, W. Li, L. Wang, T. Khoury, S. Alrawi, J. Yao, K. Xia, and D. Tan
Morphoproteomic Profile of mTOR, Ras/Raf Kinase/ERK, and NF-{kappa}B Pathways in Human Gastric Adenocarcinoma
Ann. Clin. Lab. Sci., January 1, 2008; 38(3): 195 - 209.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
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]

Home page
 Mol. Endocrinol.Home page
S. Masia, S. Alvarez, A. R. de Lera, and D. Barettino
Rapid, Nongenomic Actions of Retinoic Acid on Phosphatidylinositol-3-Kinase Signaling Pathway Mediated by the Retinoic Acid Receptor
Mol. Endocrinol., October 1, 2007; 21(10): 2391 - 2402.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
K. J. A. Davies, G. Ermak, B. A. Rothermel, M. Pritchard, J. Heitman, J. Ahnn, F. Henrique-Silva, D. Crawford, S. Canaider, P. Strippoli, et al.
Renaming the DSCR1/Adapt78 gene family as RCAN: regulators of calcineurin
FASEB J, October 1, 2007; 21(12): 3023 - 3028.
[Full Text] [PDF]

Home page
 J Mol EndocrinolHome page
C. Verga Falzacappa, E. Petrucci, V. Patriarca, S. Michienzi, A. Stigliano, E. Brunetti, V. Toscano, and S. Misiti
Thyroid hormone receptor TR{beta}1 mediates Akt activation by T3 in pancreatic {beta} cells
J. Mol. Endocrinol., February 1, 2007; 38(2): 221 - 233.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
F. Flamant, K. Gauthier, and J. Samarut
Thyroid Hormones Signaling Is Getting More Complex: STORMs Are Coming
Mol. Endocrinol., February 1, 2007; 21(2): 321 - 333.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
K. R. Short, J. Nygren, and K. S. Nair
Effect of T3-induced hyperthyroidism on mitochondrial and cytoplasmic protein synthesis rates in oxidative and glycolytic tissues in rats
Am J Physiol Endocrinol Metab, February 1, 2007; 292(2): E642 - E647.
[Abstract] [Full Text] [PDF]

Home page
 Annals of Clinical & Laboratory ScienceHome page
R. E. Brown, D. Tan, J. S. Taylor, M. Miller, J. W. Prichard, and M. M. Kott
Morphoproteomic Confirmation of Constitutively Activated mTOR, ERK, and NF-kappaB Pathways in High Risk Neuro-blastoma, with Cell Cycle and Protein Analyte Correlates
Ann. Clin. Lab. Sci., January 1, 2007; 37(2): 141 - 147.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
Y. Hiroi, H.-H. Kim, H. Ying, F. Furuya, Z. Huang, T. Simoncini, K. Noma, K. Ueki, N.-H. Nguyen, T. S. Scanlan, et al.
Rapid nongenomic actions of thyroid hormone
PNAS, September 19, 2006; 103(38): 14104 - 14109.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. Kenessey and K. Ojamaa
Thyroid Hormone Stimulates Protein Synthesis in the Cardiomyocyte by Activating the Akt-mTOR and p70S6K Pathways
J. Biol. Chem., July 28, 2006; 281(30): 20666 - 20672.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
X. Lu, F. Kambe, X. Cao, T. Yoshida, S. Ohmori, K. Murakami, T. Kaji, T. Ishii, D. Zadworny, and H. Seo
DHCR24-Knockout Embryonic Fibroblasts Are Susceptible to Serum Withdrawal-Induced Apoptosis Because of Dysfunction of Caveolae and Insulin-Akt-Bad Signaling
Endocrinology, June 1, 2006; 147(6): 3123 - 3132.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
P. M. Yen
Thyroid hormones and 3,5-diiodothyropropionic Acid: new keys for new locks.
Endocrinology, April 1, 2006; 147(4): 1598 - 1601.
[Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
N. M. Storey, S. Gentile, H. Ullah, A. Russo, M. Muessel, C. Erxleben, and D. L. Armstrong
Rapid signaling at the plasma membrane by a nuclear receptor for thyroid hormone
PNAS, March 28, 2006; 103(13): 5197 - 5201.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
F. Furuya, J. A. Hanover, and S.-y. Cheng
Activation of phosphatidylinositol 3-kinase signaling by a mutant thyroid hormone beta receptor
PNAS, February 7, 2006; 103(6): 1780 - 1785.
[Abstract] [Full Text] [PDF]

Home page
 Annals of Clinical & Laboratory ScienceHome page
R. E. Brown, P. L. Zhang, M. Lun, S. Zhu, P. K. Pellitteri, A. Law, G. C. Wood, and T. L. Kennedy
Morphoproteomic and Pharmacoproteomic Rationale for mTOR Effectors as Therapeutic Targets in Head and Neck Squamous Cell Carcinoma
Ann. Clin. Lab. Sci., January 1, 2006; 36(3): 273 - 282.
[Abstract] [Full Text] [PDF]

Home page
 Annals of Clinical & Laboratory ScienceHome page
F. Lin, P. L. Zhang, X. J. Yang, J. W. Prichard, M. Lun, and R. E. Brown
Morphoproteomic and Molecular Concomitants of an Overexpressed and Activated mTOR Pathway in Renal Cell Carcinomas
Ann. Clin. Lab. Sci., January 1, 2006; 36(3): 283 - 293.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
A. Kenessey, E. A. Sullivan, and K. Ojamaa
Nuclear localization of protein kinase C-{alpha} induces thyroid hormone receptor-{alpha}1 expression in the cardiomyocyte
Am J Physiol Heart Circ Physiol, January 1, 2006; 290(1): H381 - H389.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
L. C. Moeller, A. M. Dumitrescu, and S. Refetoff
Cytosolic Action of Thyroid Hormone Leads to Induction of Hypoxia-Inducible Factor-1{alpha} and Glycolytic Genes
Mol. Endocrinol., December 1, 2005; 19(12): 2955 - 2963.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
X. Cao, F. Kambe, X. Lu, N. Kobayashi, S. Ohmori, and H. Seo
Glutathionylation of Two Cysteine Residues in Paired Domain Regulates DNA Binding Activity of Pax-8
J. Biol. Chem., July 8, 2005; 280(27): 25901 - 25906.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
S. Incerpi
Thyroid Hormones: Rapid Reply by Surface Delivery Only
Endocrinology, July 1, 2005; 146(7): 2861 - 2863.
[Full Text] [PDF]

Home page
 EndocrinologyHome page
J. J. Bergh, H.-Y. Lin, L. Lansing, S. N. Mohamed, F. B. Davis, S. Mousa, and P. J. Davis
Integrin {alpha}V{beta}3 Contains a Cell Surface Receptor Site for Thyroid Hormone that Is Linked to Activation of Mitogen-Activated Protein Kinase and Induction of Angiogenesis
Endocrinology, July 1, 2005; 146(7): 2864 - 2871.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
X. Zhao, H. Lorenc, H. Stephenson, Y. J. Wang, D. Witherspoon, B. Katzenellenbogen, D. Pfaff, and N. Vasudevan
Thyroid hormone can increase estrogen-mediated transcription from a consensus estrogen response element in neuroblastoma cells
PNAS, March 29, 2005; 102(13): 4890 - 4895.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
L. C. Moeller, A. M. Dumitrescu, R. L. Walker, P. S. Meltzer, and S. Refetoff
Thyroid Hormone Responsive Genes in Cultured Human Fibroblasts
J. Clin. Endocrinol. Metab., February 1, 2005; 90(2): 936 - 943.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals
Copyright © 2004 by The Endocrine Society