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

J. Biol. Chem., Vol. 282, Issue 32, 23679-23686, August 10, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/32/23679    most recent M700563200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dormond, O. Articles by Briscoe, D. M. Search for Related Content PubMed PubMed Citation Articles by Dormond, O. Articles by Briscoe, D. M. Social Bookmarking                      What's this?

The Effects of mTOR-Akt Interactions on Anti-apoptotic Signaling in Vascular Endothelial Cells^*

Olivier Dormond¹, Joren C. Madsen, and David M. Briscoe²

From the Transplant Research Center, Division of Nephrology, Department of Medicine, Children's Hospital, Boston, Massachusetts 02115 and The Transplantation Biology Research Center, Massachusetts General Hospital, Boston, Massachusetts 02114

Recent studies have determined that mTOR mediates the activation of the protein kinase Akt in several cell types, but little is known about the association between mTOR and Akt in vascular endothelial cells. Furthermore, the functional significance of mTOR/Akt signaling has not been characterized in the endothelium. In these studies we treated endothelial cells with the mTOR inhibitor rapamycin, and we found that it decreases Akt phosphorylation and activity, as determined by phosphorylation of its substrate glycogen synthase kinase-3. This effect of rapamycin on Akt phosphorylation could not be demonstrated in endothelial cells transfected with a rapamycin-resistant mTOR construct. Also, in the presence of rapamycin, vascular endothelial growth factor, tumor necrosis factor, and insulin failed to phosphorylate Akt, further indicating that mTOR regulates Akt activation in endothelial cells. The activation of Akt is well established to mediate pro-survival signals. In part this is mediated via the phosphorylation and inactivation of the pro-apoptotic Akt substrates Foxo1 and Foxo3a. We find that rapamycin totally blocks vascular endothelial growth factor and Akt-inducible phosophorylation of these transcription factors in endothelial cells. Furthermore, inhibition of Akt activity by rapamycin increased the number of endothelial cells undergoing apoptosis after serum withdrawal as well as after stimulation by vascular endothelial growth factor or tumor necrosis factor. Taken together these observations demonstrate first, that mTOR regulates the phosphorylation and activation of Akt in endothelial cells and, second, that a major effect of mTOR inhibition in endothelial cells is to suppress Akt-inducible pro-survival signals.

Received for publication, January 19, 2007 , and in revised form, May 16, 2007.

^* This work was supported by National Institutes of Health Grant R01AI046756 (to D. M. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a Transplantation fellowship from the Swiss House for Advanced Research and Education (SHARE)-Novartis and the SICPA foundation.

² To whom correspondence should be addressed: Division of Nephrology, Children's Hospital Boston, 300 Longwood Ave., Boston, MA 02115. Tel.: 617-335-6129; Fax: 617-730-0130; E-mail: david.briscoe{at}childrens.harvard.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				H. A. Lane, J. M. Wood, P. M.J. McSheehy, P. R. Allegrini, A. Boulay, J. Brueggen, A. Littlewood-Evans, S.-M. Maira, G. Martiny-Baron, C. R. Schnell, et al. mTOR Inhibitor RAD001 (Everolimus) Has Antiangiogenic/Vascular Properties Distinct from a VEGFR Tyrosine Kinase Inhibitor Clin. Cancer Res., March 1, 2009; 15(5): 1612 - 1622. [Abstract] [Full Text] [PDF]

				H. Zong, C. C. Bastie, J. Xu, R. Fassler, K. P. Campbell, I. J. Kurland, and J. E. Pessin Insulin Resistance in Striated Muscle-specific Integrin Receptor {beta}1-deficient Mice J. Biol. Chem., February 13, 2009; 284(7): 4679 - 4688. [Abstract] [Full Text] [PDF]

				O. Dormond, A. G. Contreras, E. Meijer, D. Datta, E. Flynn, S. Pal, and D. M. Briscoe CD40-Induced Signaling in Human Endothelial Cells Results in mTORC2- and Akt-Dependent Expression of Vascular Endothelial Growth Factor In Vitro and In Vivo J. Immunol., December 1, 2008; 181(11): 8088 - 8095. [Abstract] [Full Text] [PDF]

				S. A. Danovi, H. H. Wong, and N. R. Lemoine Targeted therapies for pancreatic cancer Br. Med. Bull., September 1, 2008; 87(1): 97 - 130. [Abstract] [Full Text] [PDF]

				C. R. Schnell, F. Stauffer, P. R. Allegrini, T. O'Reilly, P. M.J. McSheehy, C. Dartois, M. Stumm, R. Cozens, A. Littlewood-Evans, C. Garcia-Echeverria, et al. Effects of the Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 on the Tumor Vasculature: Implications for Clinical Imaging Cancer Res., August 15, 2008; 68(16): 6598 - 6607. [Abstract] [Full Text] [PDF]

				A. Barilli, R. Visigalli, R. Sala, G. C. Gazzola, A. Parolari, E. Tremoli, S. Bonomini, A. Simon, E. I. Closs, V. Dall'Asta, et al. In human endothelial cells rapamycin causes mTORC2 inhibition and impairs cell viability and function Cardiovasc Res, June 1, 2008; 78(3): 563 - 571. [Abstract] [Full Text] [PDF]

				M. E. Cavet, E. M. Smolock, O. H. Ozturk, C. World, J. Pang, A. Konishi, and B. C. Berk Gas6-Axl Receptor Signaling Is Regulated by Glucose in Vascular Smooth Muscle Cells Arterioscler. Thromb. Vasc. Biol., May 1, 2008; 28(5): 886 - 891. [Abstract] [Full Text] [PDF]

				P. T. Jindra, A. Hsueh, L. Hong, D. Gjertson, X.-D. Shen, F. Gao, J. Dang, P. S. Mischel, W. M. Baldwin III, M. C. Fishbein, et al. Anti-MHC Class I Antibody Activation of Proliferation and Survival Signaling in Murine Cardiac Allografts J. Immunol., February 15, 2008; 180(4): 2214 - 2224. [Abstract] [Full Text] [PDF]

				P. T. Jindra, Y.-P. Jin, E. Rozengurt, and E. F. Reed HLA Class I Antibody-Mediated Endothelial Cell Proliferation via the mTOR Pathway J. Immunol., February 15, 2008; 180(4): 2357 - 2366. [Abstract] [Full Text] [PDF]

				A. Yaba, V. Bianchi, A. Borini, and J. Johnson A Putative Mitotic Checkpoint Dependent on mTOR Function Controls Cell Proliferation and Survival in Ovarian Granulosa Cells Reproductive Sciences, February 1, 2008; 15(2): 128 - 138. [Abstract] [PDF]