Rab7 prevents growth factor-independent survival by inhibiting cell-autonomous nutrient transporter expression.
Growth factor withdrawal results in the endocytosis and degradation of transporter proteins for glucose and amino acids. Here, we show that this process is under the active control of the small GTPase Rab7. In the presence of growth factor, Rab7 inhibition had no effect on nutrient transporter expression. In growth factor-deprived cells, however, blocking Rab7 function prevented the clearance of glucose and amino acid transporter proteins from the cell surface. When Rab7 was inhibited, growth factor deprived cells maintained their mitochondrial membrane potential and displayed prolonged, growth factor-independent, nutrient-dependent cell survival. Thus, Rab7 functions as a proapoptotic protein by limiting cell-autonomous nutrient uptake. Consistent with this, dominant-negative Rab7 cooperated with E1A to promote the transformation of p53(-/-) mouse embryonic fibroblasts (MEFs). These results suggest that proteins that limit nutrient transporter expression function to prevent cell-autonomous growth and survival.
Edinger
Aimee L
AL
Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Cinalli
Ryan M
RM
Thompson
Craig B
CB
D048868:Adaptor Proteins, Signal Transducing; D017500:Adenovirus E1A Proteins / Q000378:metabolism; D026905:Amino Acid Transport Systems / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D002738:Chloroquine / Q000378:metabolism; D004285:Dogs; D004622:Embryo, Mammalian; D005347:Fibroblasts; D005434:Flow Cytometry; D005508:Food Deprivation; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D051272:Glucose Transporter Type 1; D049452:Green Fluorescent Proteins; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D007377:Interleukin-3 / Q000494:pharmacology; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013997:Time Factors; D014170:Transformation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051020:bcl-X Protein; D020691:rab GTP-Binding Proteins / Q000502:physiology*; D000090802:rab7 GTP-Binding Proteins
D048868:Adaptor Proteins, Signal Transducing; D017500:Adenovirus E1A Proteins; D026905:Amino Acid Transport Systems; D000596:Amino Acids; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D002352:Carrier Proteins; D027282:Fusion Regulatory Protein 1, Heavy Chain; D051272:Glucose Transporter Type 1; D006133:Growth Substances; D007377:Interleukin-3; D008164:Luminescent Proteins; D009004:Monosaccharide Transport Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C423317:RILP protein, human; C498920:Rilp protein, mouse; C495677:SLC2A1 protein, human; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000716465:rab7 GTP-binding proteins, mouse; D049452:Green Fluorescent Proteins; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D002738:Chloroquine; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020691:rab GTP-Binding Proteins; D005947:Glucose