Molecular and Cellular Biology
Geisel School of Medicine
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 1α (HIF1α) abundance, which occurs in the absence of serum in normoxic Tsc2-deficient cells, contributes to these changes. Increased HIF1α abundance in these cells is attributed to both an increased level and the sustained translation of HIF1α 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 HIF1α 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.
Bhaskar PT, Nogueira V, Patra KC, Jeon SM, Park Y, Robey RB, Hay N. mTORC1 hyperactivity inhibits serum deprivation-induced apoptosis via increased hexokinase II and GLUT1 expression, sustained Mcl-1 expression, and glycogen synthase kinase 3beta inhibition. Mol Cell Biol. 2009 Sep;29(18):5136-47. doi: 10.1128/MCB.01946-08. Epub 2009 Jul 20. PMID: 19620286; PMCID: PMC2738274.
Dartmouth Digital Commons Citation
Bhaskar, Prashanth T.; Nogueira, Veronique; Patra, Krushna C.; Jeon, Sang-Min; Park, Youngkyu; Robey, R. Brooks; and Hay, Nissim, "mTORC1 Hyperactivity Inhibits Serum Deprivation-Induced Apoptosis via Increased Hexokinase II and GLUT1 Expression, Sustained Mcl-1 Expression, and Glycogen Synthase Kinase 3β Inhibition" (2009). Dartmouth Scholarship. 1516.