Induction of TNF-sensitive cellular phenotype by c-myc involves p53 and impaired NF-κB activation

被引:106
作者
Klefstrom, J
Arighi, E
Littlewood, T
Jäättelä, M
Saksela, E
Evan, GI
Alitalo, K
机构
[1] Univ Helsinki, Haartman Inst, Mol Canc Biol Lab, FIN-00014 Helsinki, Finland
[2] Imperial Canc Res Fund, Biochem Cell Nucleus Lab, London WC2A 3PX, England
[3] Danish Canc Soc, Apoptosis Lab, DK-2100 Copenhagen, Denmark
关键词
apoptosis; Myc; NF-kappa B; p53; tumor necrosis factor;
D O I
10.1093/emboj/16.24.7382
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Normal fibroblasts are resistant to the cytotoxic action of tumor necrosis factor (TNF), but are rendered TNF-sensitive upon deregulation of c-Myc. To assess if oncoproteins induce the cytotoxic TNF activity by modulating TNF signaling, we investigated the TNF-elicited signalling responses in fibroblasts containing a conditionally active c-Myc protein. In association with cell death, c-Myc impaired TNF-induced activation of phospholipase A(2), JNK protein kinase and cell survival-signaling-associated NF-kappa B activity in the cells. Unlike other TNF-induced signal, TNF-induced accumulation of the wild-type p53 mRNA and protein was not inhibited by c-Myc. TNF, with c-Myc, induced apoptosis in mouse primary fibroblasts but only weakly in p53-deficient primary fibroblasts. The C-terminal domain of p53, which is a transacting dominant inhibitor of wild-type p53, failed to inhibit apoptosis by c-Myc and TNF, suggesting that the cell death was not dependent on the transcription-activating function of p53. Taken together, the present findings show that the cytotoxic activity of TNF towards oncoprotein-expressing cells involves p53 and an impaired signaling for survival in such cells.
引用
收藏
页码:7382 / 7392
页数:11
相关论文
共 53 条
[1]   INCREASE OF VULNERABILITY TO LYMPHOTOXIN IN CELLS INFECTED BY VESICULAR STOMATITIS-VIRUS AND ITS FURTHER AUGMENTATION BY INTERFERON [J].
ADERKA, D ;
NOVICK, D ;
HAHN, T ;
FISCHER, DG ;
WALLACH, D .
CELLULAR IMMUNOLOGY, 1985, 92 (02) :218-225
[2]   THE C-MYC PROTEIN INDUCES CELL-CYCLE PROGRESSION AND APOPTOSIS THROUGH DIMERIZATION WITH MAX [J].
AMATI, B ;
LITTLEWOOD, TD ;
EVAN, GI ;
LAND, H .
EMBO JOURNAL, 1993, 12 (13) :5083-5087
[3]   An essential role for NF-kappa B in preventing TNF-alpha-induced cell death [J].
Beg, AA ;
Baltimore, D .
SCIENCE, 1996, 274 (5288) :782-784
[4]   Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death [J].
Boldin, MP ;
Goncharov, TM ;
Goltsev, YV ;
Wallach, D .
CELL, 1996, 85 (06) :803-815
[5]   INDUCERS OF THE HEAT-SHOCK RESPONSE STIMULATE PHOSPHOLIPASE-C AND PHOSPHOLIPASE-A2 ACTIVITY IN MAMMALIAN-CELLS [J].
CALDERWOOD, SK ;
STEVENSON, MA .
JOURNAL OF CELLULAR PHYSIOLOGY, 1993, 155 (02) :248-256
[6]   ENDOTOXIN-INDUCED SERUM FACTOR THAT CAUSES NECROSIS OF TUMORS [J].
CARSWELL, EA ;
OLD, LJ ;
KASSEL, RL ;
GREEN, S ;
FIORE, N ;
WILLIAMSON, B .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1975, 72 (09) :3666-3670
[7]   INDUCTION BY E1A ONCOGENE EXPRESSION OF CELLULAR-SUSCEPTIBILITY TO LYSIS BY TNF [J].
CHEN, MJ ;
HOLSKIN, B ;
STRICKLER, J ;
GORNIAK, J ;
CLARK, MA ;
JOHNSON, PJ ;
MITCHO, M ;
SHALLOWAY, D .
NATURE, 1987, 330 (6148) :581-583
[8]   Oxidative stress mediates synthesis of cytosolic phospholipase A(2) after UVB injury [J].
Chen, X ;
Gresham, A ;
Morrison, A ;
Pentland, AP .
BIOCHIMICA ET BIOPHYSICA ACTA-LIPIDS AND LIPID METABOLISM, 1996, 1299 (01) :23-33
[9]   INDUCTION OF APOPTOSIS BY THE BCL-2 HOMOLOG BAK [J].
CHITTENDEN, T ;
HARRINGTON, EA ;
OCONNOR, R ;
FLEMINGTON, C ;
LUTZ, RJ ;
EVAN, GI ;
GUILD, BC .
NATURE, 1995, 374 (6524) :733-736
[10]   A cytokine-responsive I kappa B kinase that activates the transcription factor NF-kappa B [J].
DiDonato, JA ;
Hayakawa, M ;
Rothwarf, DM ;
Zandi, E ;
Karin, M .
NATURE, 1997, 388 (6642) :548-554