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Molecular and Cellular Biology, December 2000, p. 8983-8995, Vol. 20, No. 23
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Insulin-Like Growth Factor-Mediated Muscle Cell Survival: Central Roles for Akt and Cyclin-Dependent Kinase Inhibitor p21

Margaret A. Lawlor and Peter Rotwein*

Molecular Medicine Division, Oregon Health Sciences University, Portland, Oregon 97201-3098

Received 6 April 2000/Returned for modification 24 May 2000/Accepted 28 August 2000

Polypeptide growth factors activate specific transmembrane receptors, leading to the induction of multiple intracellular signal transduction pathways which control cell function and fate. Recent studies have shown that growth factors promote cell survival by stimulating the serine-threonine protein kinase Akt, which appears to function primarily as an antiapoptotic agent by inactivating death-promoting molecules. We previously established C2 muscle cell lines lacking endogenous expression of insulin-like growth factor II (IGF-II). These cells underwent apoptotic death in low-serum differentiation medium but could be maintained as viable myoblasts by IGF analogues that activated the IGF-I receptor or by unrelated growth factors such as platelet-derived growth factor BB (PDGF-BB). Here we show that IGF-I promotes muscle cell survival through Akt-mediated induction of the cyclin-dependent kinase inhibitor p21. Treatment of myoblasts with IGF-I or transfection with an inducible Akt maintained muscle cell survival and enhanced production of p21, and ectopic expression of p21 was able to sustain viability in the absence of growth factors. Blocking of p21 protein accumulation through a specific p21 antisense cDNA prevented survival regulated by IGF-I or Akt but did not block muscle cell viability mediated by PDGF-BB. Our results define Akt as an intermediate and p21 as a critical effector of an IGF-controlled myoblast survival pathway that is active during early myogenic differentiation and show that growth factors are able to maintain cell viability by inducing expression of pro-survival molecules.

* Corresponding author. Mailing address: Oregon Health Sciences University, Molecular Medicine Division, 3181 S.W. Sam Jackson Park Rd., Mail code: NRC3, Portland, OR 97201-3098. Phone: (503) 494-0536. Fax: (503) 494-7368. E-mail: rotweinp{at}ohsu.edu.

Molecular and Cellular Biology, December 2000, p. 8983-8995, Vol. 20, No. 23
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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