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Molecular and Cellular Biology, October 2003, p. 7315-7328, Vol. 23, No. 20
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.20.7315-7328.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Akt-Directed Glucose Metabolism Can Prevent Bax Conformation Change and Promote Growth Factor-Independent Survival

Jeffrey C. Rathmell, Casey J. Fox, David R. Plas, Peter S. Hammerman, Ryan M. Cinalli, and Craig B. Thompson*

Departments of Cancer Biology and Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Received 16 December 2002/ Returned for modification 1 April 2003/ Accepted 18 July 2003

The serine/threonine kinase Akt is a component of many receptor signal transduction pathways and can prevent cell death following growth factor withdrawal. Here, we show that Akt inhibition of cell death is not dependent on new protein translation. Instead, Akt inhibition of cell death requires glucose hydrolysis through glycolysis. Akt was found to regulate multiple steps in glycolysis via posttranscriptional mechanisms that included localization of the glucose transporter, Glut1, to the cell surface and maintenance of hexokinase function in the absence of extrinsic factors. To test the role of glucose uptake and phosphorylation in growth factor-independent survival, cells were transfected with Glut1 and hexokinase 1 (Glut1/HK1) cells. Glut1/HK1 cells accumulated Glut1 on the cell surface and had high glucose uptake capacity similar to that of cells with constitutively active Akt (mAkt). Unlike mAkt-expressing cells, however, they did not consume more glucose, did not maintain prolonged phosphofructokinase-1 protein levels and activity, and did not maintain pentose phosphate shuttle activity in the absence of growth factor. Nevertheless, expression of Glut1 and HK1 promoted increased cytosolic NADH and NADPH levels relative to those of the control cells upon growth factor withdrawal, prevented activation of Bax, and promoted growth factor-independent survival. These data indicate that Bax conformation is sensitive to glucose metabolism and that maintaining glucose uptake and phosphorylation can promote cell survival in the absence of growth factor. Furthermore, Akt required glucose and the ability to perform glycolysis to prevent Bax activation. The prevention of Bax activation by posttranscriptional regulation of glucose metabolism may, therefore, be a required aspect of the ability of Akt to maintain long-term cell survival in the absence of growth factors.

* Corresponding author. Mailing address: Abramson Family Cancer Research Institute, University of Pennsylvania, BRB II/III, Room 450, 421 Curie Blvd., Philadelphia, PA 19104. Phone: (215) 746-5515. Fax: (215) 746-5511. E-mail: craig{at}mail.med.upenn.edu.

Molecular and Cellular Biology, October 2003, p. 7315-7328, Vol. 23, No. 20
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.20.7315-7328.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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