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Molecular and Cellular Biology, July 2004, p. 6231-6240, Vol. 24, No. 14
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.14.6231-6240.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Deletion of Ribosomal S6 Kinases Does Not Attenuate Pathological, Physiological, or Insulin-Like Growth Factor 1 Receptor-Phosphoinositide 3-Kinase-Induced Cardiac Hypertrophy

Julie R. McMullen,1* Tetsuo Shioi,1 Li Zhang,1 Oleg Tarnavski,1 Megan C. Sherwood,2 Adam L. Dorfman,2 Sarah Longnus,1 Mario Pende,3 Kathleen A. Martin,4 John Blenis,4 George Thomas,3 and Seigo Izumo1

Beth Israel Deaconess Medical Center,1 Department of Cell Biology, Harvard Medical School,4 Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts,2 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland3

Received 12 April 2004/ Returned for modification 23 April 2004/ Accepted 28 April 2004

Ribosomal S6 kinases (S6Ks) have been depicted as critical effectors downstream of growth factor pathways, which play an important role in the regulation of protein synthesis by phosphorylating the ribosomal protein, S6. The goal of this study was to determine whether S6Ks regulate heart size, are critical for the induction of cardiac hypertrophy in response to a pathological or physiological stimulus, and whether S6Ks are critical downstream effectors of the insulin-like growth factor 1 (IGF1)-phosphoinositide 3-kinase (PI3K) pathway. For this purpose, we generated and characterized cardiac-specific S6K1 and S6K2 transgenic mice and subjected S6K1–/–, S6K2–/–, and S6K1–/– S6K2–/– mice to a pathological stress (aortic banding) or a physiological stress (exercise training). To determine the genetic relationship between S6Ks and the IGF1-PI3K pathway, S6K transgenic and knockout mice were crossed with cardiac-specific transgenic mice overexpressing the IGF1 receptor (IGF1R) or PI3K mutants. Here we show that overexpression of S6K1 induced a modest degree of hypertrophy, whereas overexpression of S6K2 resulted in no obvious cardiac phenotype. Unexpectedly, deletion of S6K1 and S6K2 had no impact on the development of pathological, physiological, or IGF1R-PI3K-induced cardiac hypertrophy. These studies suggest that S6Ks alone are not essential for the development of cardiac hypertrophy.

* Corresponding author. Mailing address: Beth Israel Deaconess Medical Center, Cardiovascular Division, 330 Brookline Ave., SL-408, Boston, MA 02215. Phone: (617) 667-4863. Fax: (617) 975-5268. E-mail: jmcmulle{at}bidmc.harvard.edu.

Molecular and Cellular Biology, July 2004, p. 6231-6240, Vol. 24, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.14.6231-6240.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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