Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21(Cip1).
Under serum-free conditions, rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), induces apoptosis of cells lacking functional p53. Cells expressing wild-type p53 or p21(Cip1)arrest in G1 and remain viable. In cells lacking functional p53, rapamycin or amino acid deprivation induces rapid and sustained activation of apoptosis signal-regulating kinase 1 (ASK1), c-Jun N-terminal kinase, and elevation of phosphorylated c-Jun that results in apoptosis. This stress response depends on expression of eukaryotic initiation factor 4E binding protein 1 and is suppressed by p21(Cip1) independent of cell cycle arrest. Rapamycin induces p21(Cip1) binding to ASK1, suppressing kinase activity and attenuating cellular stress. These results suggest that inhibition of mTOR triggers a potentially lethal response that is prevented only in cells expressing p21(Cip1).
Huang
Shile
S
Department of Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Shu
Lili
L
Dilling
Michael B
MB
Easton
John
J
Harwood
Franklin C
FC
Ichijo
Hidenori
H
Houghton
Peter J
PJ
D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D002460:Cell Line; D016895:Culture Media, Serum-Free; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004789:Enzyme Activation; D005347:Fibroblasts; D016193:G1 Phase; D005786:Gene Expression Regulation; D006801:Humans; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000473:pathology; D020123:Sirolimus / Q000494:pharmacology*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C493956:CDKN1A protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016895:Culture Media, Serum-Free; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D016755:Proto-Oncogene Proteins c-jun; D016159:Tumor Suppressor Protein p53; D020928:Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482858:MAP3K5 protein, human; D020123:Sirolimus