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Molecular and Cellular Biology, September 2009, p. 5104-5114, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.00465-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Mechanoregulation of Proliferation{triangledown}

Xiaogang Jiang,1,{dagger} Paul F. Austin,1 Robert A. Niederhoff,1 Scott R. Manson,1 Jacob J. Riehm,1 Brian L. Cook,1,{ddagger} Gina Pengue,1 Kanchan Chitaley,3 Keiko Nakayama,4 Keiichi I. Nakayama,5 and Steven J. Weintraub1,2*

Division of Urology and Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri 63110,1 Department of Internal Medicine, St. Louis VA Medical Center, John Cochran Division, 915 North Grand Blvd., St. Louis, Missouri 63106,2 Department of Urology, University of Washington, Box 358050, 815 Mercer Street, Seattle, Washington 98109,3 Center for Translational and Advanced Animal Research on Human Diseases, Tohoku University School of Medicine, Sendai, Japan,4 Department of Molecular and Cellular Biology, Medical Institute of Bioregulation Kyushu University, Fukuoka, Japan5

Received 9 April 2009/ Returned for modification 26 May 2009/ Accepted 30 June 2009

The proliferation of all nontransformed adherent cells is dependent upon the development of mechanical tension within the cell; however, little is known about the mechanisms by which signals regulated by mechanical tension are integrated with those regulated by growth factors. We show here that Skp2, a component of a ubiquitin ligase complex that mediates the degradation of several proteins that inhibit proliferation, is upregulated when increased mechanical tension develops in intact smooth muscle and that its upregulation is critical for the smooth muscle proliferative response to increased mechanical tension. Notably, whereas growth factors regulate Skp2 at the level of protein stability, we found that mechanical tension regulates Skp2 at the transcriptional level. Importantly, we demonstrate that the calcium-regulated transcription factor NFATc1 is a critical mediator of the effect of increased mechanical tension on Skp2 transcription. These findings identify Skp2 as a node at which signals from mechanical tension and growth factors are integrated to regulate proliferation, and they define calcium-NFAT-Skp2 signaling as a critical pathway in the mechanoregulation of proliferation.

* Corresponding author. Mailing address: Department of Internal Medicine, St. Louis VA Medical Center, John Cochran Division, 915 North Grand Blvd., St. Louis, MO 63106. Phone: (314) 652-4100, ext. 55298. Fax: (314) 362-5932. E-mail: sjweintraub{at}gmail.com

{triangledown} Published ahead of print on 13 July 2009.

{dagger} Present address: Department of Urology, University of Washington, Box 358050, 815 Mercer Street, Seattle, WA 98109.

{ddagger} Present address: MIT Department of Biological Engineering, 500 Technology Square, NE47-380, Cambridge, MA 02139.

Molecular and Cellular Biology, September 2009, p. 5104-5114, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.00465-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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