Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21Cip1

Shile Huang, Lili Shu, Michael B. Dilling, John Easton, Franklin C. Harwood, Hidenori Ichijo, Peter J Houghton

Research output: Contribution to journalArticle

193 Citations (Scopus)

Abstract

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 p21Cip1arrest 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 p21Cip1 independent of cell cycle arrest. Rapamycin induces p21Cip1 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 p21Cip1.

Original languageEnglish (US)
Pages (from-to)1491-1501
Number of pages11
JournalMolecular Cell
Volume11
Issue number6
DOIs
StatePublished - Jun 1 2003
Externally publishedYes

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Sirolimus
Apoptosis
MAP Kinase Kinase Kinase 5
Eukaryotic Initiation Factor-4E
JNK Mitogen-Activated Protein Kinases
Cell Cycle Checkpoints
Carrier Proteins
Phosphotransferases
Amino Acids
Serum

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21Cip1 . / Huang, Shile; Shu, Lili; Dilling, Michael B.; Easton, John; Harwood, Franklin C.; Ichijo, Hidenori; Houghton, Peter J.

In: Molecular Cell, Vol. 11, No. 6, 01.06.2003, p. 1491-1501.

Research output: Contribution to journalArticle

Huang, Shile ; Shu, Lili ; Dilling, Michael B. ; Easton, John ; Harwood, Franklin C. ; Ichijo, Hidenori ; Houghton, Peter J. / Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21Cip1 In: Molecular Cell. 2003 ; Vol. 11, No. 6. pp. 1491-1501.
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