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Molecular and Cellular Biology, September 2009, p. 5136-5147, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.01946-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

mTORC1 Hyperactivity Inhibits Serum Deprivation-Induced Apoptosis via Increased Hexokinase II and GLUT1 Expression, Sustained Mcl-1 Expression, and Glycogen Synthase Kinase 3β Inhibition{triangledown}

Prashanth T. Bhaskar,1,{dagger} Veronique Nogueira,1,{dagger} Krushna C. Patra,1 Sang-Min Jeon,1 Youngkyu Park,1 R. Brooks Robey,2,3,4 and Nissim Hay1*

Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607,1 Departments of Medicine,2 Physiology, Dartmouth Medical School, Lebanon, New Hampshire 03755,3 White River Junction VA Medical Center, White River Junction, Vermont 050094

Received 23 December 2008/ Returned for modification 21 February 2009/ Accepted 8 July 2009

The current concept is that Tsc-deficient cells are sensitized to apoptosis due to the inhibition of Akt activity by the negative feedback mechanism induced by the hyperactive mTORC1. Unexpectedly, however, we found that Tsc1/2-deficient cells exhibit increased resistance to serum deprivation-induced apoptosis. mTORC1 hyperactivity contributes to the apoptotic resistance of serum-deprived Tsc1/2-deficient cells in part by increasing the growth factor-independent expression of hexokinase II (HKII) and GLUT1. mTORC1-mediated increase in hypoxia-inducible factor 1{alpha} (HIF1{alpha}) abundance, which occurs in the absence of serum in normoxic Tsc2-deficient cells, contributes to these changes. Increased HIF1{alpha} abundance in these cells is attributed to both an increased level and the sustained translation of HIF1{alpha} mRNA. Sustained glycogen synthase kinase 3β inhibition and Mcl-1 expression also contribute to the apoptotic resistance of Tsc2-deficient cells to serum deprivation. The inhibition of mTORC1 activity by either rapamycin or Raptor knockdown cannot resensitize these cells to serum deprivation-induced apoptosis because of elevated Akt activity that is an indirect consequence of mTORC1 inhibition. However, the increased HIF1{alpha} abundance and the maintenance of Mcl-1 protein expression in serum-deprived Tsc2–/– cells are dependent largely on the hyperactive eIF4E in these cells. Consistently, the reduction of eIF4E levels abrogates the resistance of Tsc2–/– cells to serum deprivation-induced apoptosis.

* Corresponding author. Mailing address: University of Illinois at Chicago, Department of Biochemistry and Molecular Genetics (M/C 669), College of Medicine, 900 S. Ashland Ave., Chicago, IL 60607. Phone: (312) 355-1684. Fax: (312) 355-2032. E-mail: nhay{at}uic.edu

{triangledown} Published ahead of print on 20 July 2009.

{dagger} These authors contributed equally.

Molecular and Cellular Biology, September 2009, p. 5136-5147, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.01946-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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