An activated mTOR mutant supports growth factor-independent, nutrient-dependent cell survival.
In yeast, TOR couples cellular growth and metabolism to the availability of extracellular nutrients. In contrast, mammalian TOR kinase activity has been reported to be regulated by growth factor stimulation via the PI3K/Akt pathway. Consistent with this, growth factor deprivation results in dephosphorylation of the mTOR target proteins p70S6k and 4EBP1 in the face of abundant extracellular nutrients. To determine whether the activation of mTOR was sufficient to support cell survival in the absence of other growth factor-mediated signal transduction, we evaluated the ability of a growth factor-independent mTOR mutant, DeltaTOR, to protect cells from growth factor deprivation. DeltaTOR- but not wild-type mTOR-expressing cells were protected from many of the sequelae of growth factor deprivation including amino-acid transporter degradation, reduction of the glycolytic rate, cellular atrophy, decreased mitochondrial membrane potential, and Bax activation. Furthermore, DeltaTOR expression increased growth factor-independent, nutrient-dependent cell survival and enhanced the ability of p53-/- MEFs to form colonies in soft agar. These results suggest that activating mutations of mTOR can contribute to apoptotic resistance and might contribute to cellular transformation.
Edinger
Aimee L
AL
Abramson Family Cancer Research Institute, University of Pennsylvania, 450 BRB II/III, 421 Curie Blvd, Philadelphia, PA 19104, USA.
Thompson
Craig B
CB
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D002470:Cell Survival; D039642:Eukaryotic Initiation Factors; D006133:Growth Substances / Q000378:metabolism*; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000737:chemistry; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
D048868:Adaptor Proteins, Signal Transducing; C494827:Bax protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D006133:Growth Substances; D007377:Interleukin-3; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; D051028:bcl-2-Associated X Protein; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus