Inhibition of the anti-apoptotic PI(3)K/Akt/Bad pathway by stress.
The initiation of apoptosis often transpires in the presence of agents that regulate cell survival. This study evaluated the effects of stress-induced ceramide on the anti-apoptotic activity of the phosphoinositide-3 kinase [PI(3)K] pathway. PI(3)K activity is directly down-regulated by stress-induced ceramide in a dose-dependent manner with rapid kinetics and high specificity. Ceramide inhibition of PI(3)K is dependent on acid-sphingomyelinase. Down-regulation of PI(3)K by ceramide results in inhibition of the kinase Akt and decreased phosphorylation of the death effector Bad. Thus, ceramide levels could act as a general apoptotic rheostat controlling cell survival by regulating PI(3)K anti-apoptotic effector mechanisms.
Zundel
W
W
Cancer Biology Program, Mayer Cancer Biology Research Laboratory, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California 94305-5468 USA.
Giaccia
A
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002460:Cell Line; D002461:Cell Line, Transformed; D002518:Ceramides / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000528:radiation effects; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000528:radiation effects; D005720:Gamma Rays; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000528:radiation effects; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D013312:Stress, Physiological / Q000201:enzymology* / Q000473:pathology; D014466:Ultraviolet Rays; D051025:bcl-Associated Death Protein
D002352:Carrier Proteins; D002518:Ceramides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D051025:bcl-Associated Death Protein; C494819:BAD protein, human; C494821:Bad protein, rat; C494918:AKT1 protein, human; C494920:Akt1 protein, rat