Growth control under stress: mTOR regulation through the REDD1-TSC pathway.
Dysregulated signaling by the checkpoint kinase TOR (target of rapamycin) has been linked to numerous human cancers. The tuberous sclerosis tumor suppressors TSC1 and TSC2 form a protein complex that integrates and transmits cellular growth factor and stress signals to negatively regulate TOR activity. Several recent reports have identified the stress response gene REDD1 as an essential regulator of TOR activity through the TSC1/2 complex in both Drosophila and mammalian cells. REDD1 is induced in response both to hypoxia and energy stress, and cells that lack REDD1 exhibit highly defective TOR regulation in response to either of these stress signals. While the precise mechanism of REDD1 function remains to be determined, the finding that REDD1-dependent TOR regulation contributes to cell growth/cell size control in flies and mammals suggests that abnormalities of REDD1-mediated signaling might disrupt energy homeostasis and/or promote tumorigenesis.
Ellisen
Leif W
LW
Harvard Medical School, MGH Cancer Center, Boston, Massachusettes 02114, USA. ellisen@helix.mgh.harvard.edu
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018384:Oxidative Stress / Q000502:physiology*; D011494:Protein Kinases / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000502:physiology*
C469991:DDIT4 protein, human; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D014157:Transcription Factors; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases