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

doi:10.1016/S1097-2765(03)00180-1

Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21^Cip1

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

Research output: Contribution to journal › Article › peer-review

208 Scopus citations

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 p21^Cip1arrest 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.

Original language	English (US)
Pages (from-to)	1491-1501
Number of pages	11
Journal	Molecular Cell
Volume	11
Issue number	6
DOIs	https://doi.org/10.1016/S1097-2765(03)00180-1
State	Published - Jun 1 2003
Externally published	Yes

ASJC Scopus subject areas

Molecular Biology
Cell Biology

Access to Document

10.1016/S1097-2765(03)00180-1

Cite this

@article{97ff4bee9a4d4060b241d66bfbd1004d,

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

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.",

author = "Shile Huang and Lili Shu and Dilling, {Michael B.} and John Easton and Harwood, {Franklin C.} and Hidenori Ichijo and Houghton, {Peter J.}",

note = "Funding Information: We thank Drs. Tyler Jacks, Michael Karin, and Charles Sherr for kind gifts of MEF cell lines. We also thank Drs. Robert T. Abraham, Minora Asada, Michael J. Birrer, Wafik El-Deiry, Greg Hanna, Tom Maniatis, and Jonathan Whitfield for generously providing adenoviral recombinants or plasmid constructs. We thank, also, Sharon Naron for help in preparing this manuscript. This work was supported in part by USPHS awards CA77776 (P.J.H.), CA23099 (P.J.H.), CA96696 (P.J.H.), and CA21765 (Cancer Center Support Grant), by a grant from Wyeth-Ayerst Company (P.J.H), and by the American Lebanese Syrian Associated Charities (ALSAC).",

year = "2003",

month = jun,

day = "1",

doi = "10.1016/S1097-2765(03)00180-1",

language = "English (US)",

volume = "11",

pages = "1491--1501",

journal = "Molecular Cell",

issn = "1097-2765",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21Cip1

AU - Huang, Shile

AU - Shu, Lili

AU - Dilling, Michael B.

AU - Easton, John

AU - Harwood, Franklin C.

AU - Ichijo, Hidenori

AU - Houghton, Peter J.

N1 - Funding Information: We thank Drs. Tyler Jacks, Michael Karin, and Charles Sherr for kind gifts of MEF cell lines. We also thank Drs. Robert T. Abraham, Minora Asada, Michael J. Birrer, Wafik El-Deiry, Greg Hanna, Tom Maniatis, and Jonathan Whitfield for generously providing adenoviral recombinants or plasmid constructs. We thank, also, Sharon Naron for help in preparing this manuscript. This work was supported in part by USPHS awards CA77776 (P.J.H.), CA23099 (P.J.H.), CA96696 (P.J.H.), and CA21765 (Cancer Center Support Grant), by a grant from Wyeth-Ayerst Company (P.J.H), and by the American Lebanese Syrian Associated Charities (ALSAC).

PY - 2003/6/1

Y1 - 2003/6/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0038094504&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038094504&partnerID=8YFLogxK

U2 - 10.1016/S1097-2765(03)00180-1

DO - 10.1016/S1097-2765(03)00180-1

M3 - Article

C2 - 12820963

AN - SCOPUS:0038094504

SN - 1097-2765

VL - 11

SP - 1491

EP - 1501

JO - Molecular Cell

JF - Molecular Cell

IS - 6

ER -

Sustained activation of the JNK cascade and rapamycin-induced apoptosis are suppressed by p53/p21^Cip1

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this