HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 276, Issue 39, 36079-36082, September 28, 2001

This Article Full Text Full Text (PDF) All Versions of this Article: 276/39/36079    most recent C100406200v1 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Erbay, E. Articles by Chen, J. Search for Related Content PubMed PubMed Citation Articles by Erbay, E. Articles by Chen, J.

ACCELERATED PUBLICATION
The Mammalian Target of Rapamycin Regulates C2C12 Myogenesis via a Kinase-independent Mechanism^*

Ebru Erbay and Jie Chen

From the Department of Cell and Structural Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801

Rapamycin inhibits differentiation of mouse C2C12 myoblasts, a tissue culture model for skeletal muscle differentiation. The mechanism by which a rapamycin-sensitive signaling pathway regulates myogenesis is largely unknown. The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation, but its role in myogenesis has not been examined directly. Here we report the investigation of the function of mTOR and its downstream effectors in muscle differentiation. Rapamycin exerts an inhibitory effect on C2C12 myogenesis at different stages, implying that a rapamycin-sensitive pathway may be required for multiple processes during muscle differentiation. The mTOR protein level increases 10-fold during differentiation, via a post-transcriptional mechanism. As the first direct demonstration of the essential role of mTOR in muscle differentiation, we show that a rapamycin-resistant mTOR, but not S6 kinase 1, can rescue rapamycin-inhibited myogenesis. Remarkably, the myogenic function of mTOR does not require its kinase activity. Two downstream effectors of the rapamycin-sensitive pathway, S6 kinase 1 and eIF4E-binding protein 1, undergo differential regulation during myogenesis, but neither protein is the relevant effector for the myogenic signaling of mTOR. Taken together, our observations suggest a novel mTOR signaling mechanism essential for skeletal muscle differentiation.

This article has been cited by other articles:

				A.-L. Wu, J.-H. Kim, C. Zhang, T. G. Unterman, and J. Chen Forkhead Box Protein O1 Negatively Regulates Skeletal Myocyte Differentiation through Degradation of Mammalian Target of Rapamycin Pathway Components Endocrinology, March 1, 2008; 149(3): 1407 - 1414. [Abstract] [Full Text] [PDF]

				M.-S. Yoon and J. Chen PLD regulates myoblast differentiation through the mTOR-IGF2 pathway J. Cell Sci., February 1, 2008; 121(3): 282 - 289. [Abstract] [Full Text] [PDF]

				W. Li, G. Wu, and Y. Wan The dual effects of Cdh1/APC in myogenesis FASEB J, November 1, 2007; 21(13): 3606 - 3617. [Abstract] [Full Text] [PDF]

				Y. Zhang, C. J. Billington Jr., D. Pan, and T. P. Neufeld Drosophila Target of Rapamycin Kinase Functions as a Multimer Genetics, January 1, 2006; 172(1): 355 - 362. [Abstract] [Full Text] [PDF]

				I.-H. Park and J. Chen Mammalian Target of Rapamycin (mTOR) Signaling Is Required for a Late-stage Fusion Process during Skeletal Myotube Maturation J. Biol. Chem., September 9, 2005; 280(36): 32009 - 32017. [Abstract] [Full Text] [PDF]

				F. Tremblay, A. Gagnon, A. Veilleux, A. Sorisky, and A. Marette Activation of the Mammalian Target of Rapamycin Pathway Acutely Inhibits Insulin Signaling to Akt and Glucose Transport in 3T3-L1 and Human Adipocytes Endocrinology, March 1, 2005; 146(3): 1328 - 1337. [Abstract] [Full Text] [PDF]

				J. E. Kim and J. Chen Regulation of Peroxisome Proliferator-Activated Receptor-{gamma} Activity by Mammalian Target of Rapamycin and Amino Acids in Adipogenesis Diabetes, November 1, 2004; 53(11): 2748 - 2756. [Abstract] [Full Text] [PDF]

				S. Huang, L. Shu, J. Easton, F. C. Harwood, G. S. Germain, H. Ichijo, and P. J. Houghton Inhibition of Mammalian Target of Rapamycin Activates Apoptosis Signal-regulating Kinase 1 Signaling by Suppressing Protein Phosphatase 5 Activity J. Biol. Chem., August 27, 2004; 279(35): 36490 - 36496. [Abstract] [Full Text] [PDF]

				E. M. Wilson, J. Tureckova, and P. Rotwein Permissive Roles of Phosphatidyl Inositol 3-Kinase and Akt in Skeletal Myocyte Maturation Mol. Biol. Cell, February 1, 2004; 15(2): 497 - 505. [Abstract] [Full Text] [PDF]

				D. C. Fingar, C. J. Richardson, A. R. Tee, L. Cheatham, C. Tsou, and J. Blenis mTOR Controls Cell Cycle Progression through Its Cell Growth Effectors S6K1 and 4E-BP1/Eukaryotic Translation Initiation Factor 4E Mol. Cell. Biol., January 1, 2004; 24(1): 200 - 216. [Abstract] [Full Text] [PDF]

				E. Erbay, I.-H. Park, P. D. Nuzzi, C. J. Schoenherr, and J. Chen IGF-II transcription in skeletal myogenesis is controlled by mTOR and nutrients J. Cell Biol., December 8, 2003; 163(5): 931 - 936. [Abstract] [Full Text] [PDF]

				J. D. Parkington, A. P. Siebert, N. K. LeBrasseur, and R. A. Fielding Differential activation of mTOR signaling by contractile activity in skeletal muscle Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2003; 285(5): R1086 - R1090. [Abstract] [Full Text] [PDF]

				M. L. Hribal, J. Nakae, T. Kitamura, J. R. Shutter, and D. Accili Regulation of insulin-like growth factor-dependent myoblast differentiation by Foxo forkhead transcription factors J. Cell Biol., August 18, 2003; 162(4): 535 - 541. [Abstract] [Full Text] [PDF]

				J. A. Lehman, V. Calvo, and J. Gomez-Cambronero Mechanism of Ribosomal p70S6 Kinase Activation by Granulocyte Macrophage Colony-stimulating Factor in Neutrophils: COOPERATION OF A MEK-RELATED, THR421/SER424 KINASE AND A RAPAMYCIN-SENSITIVE, mTOR-RELATED THR389 KINASE J. Biol. Chem., July 18, 2003; 278(30): 28130 - 28138. [Abstract] [Full Text] [PDF]

				L. Shu, X. Zhang, and P. J. Houghton Myogenic Differentiation Is Dependent on Both the Kinase Function and the N-terminal Sequence of Mammalian Target of Rapamycin J. Biol. Chem., May 3, 2002; 277(19): 16726 - 16732. [Abstract] [Full Text] [PDF]

				T. K. Bratanova-Tochkova, H. Cheng, S. Daniel, S. Gunawardana, Y.-J. Liu, J. Mulvaney-Musa, T. Schermerhorn, S. G. Straub, H. Yajima, and G. W.G. Sharp Triggering and Augmentation Mechanisms, Granule Pools, and Biphasic Insulin Secretion Diabetes, February 1, 2002; 51(90001): S83 - 90. [Abstract] [Full Text] [PDF]