NF-κB activation by camptothecin -: A linkage between nuclear DNA damage and cytoplasmic signaling events

被引:151
作者
Huang, TT
Wuerzberger-Davis, SM
Seufzer, BJ
Shumway, SD
Kurama, T
Boothman, DA
Miyamoto, S
机构
[1] Univ Wisconsin, Sch Med, Dept Pharmacol, Madison, WI 53792 USA
[2] Univ Wisconsin, Program Mol & Cellular Pharmacol, Madison, WI 53792 USA
[3] Univ Wisconsin, Human Canc Biol Program, Madison, WI 53792 USA
[4] Univ Wisconsin, Program Cellular & Mol Biol, Madison, WI 53792 USA
[5] Case Western Reserve Univ, Dept Radiat Oncol, Cleveland, OH 44106 USA
[6] Case Western Reserve Univ, Dept Pharmacol, Lab Mol Stress Responses, Cleveland, OH 44106 USA
关键词
D O I
10.1074/jbc.275.13.9501
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
Activation of the transcription factor NF-kappa B by extracellular signals involves its release from the inhibitor protein I kappa B alpha in the cytoplasm and subsequent nuclear translocation. NF-kappa B can also be activated by the anticancer agent camptothecin (CPT), which inhibits DNA topoisomerase (Topo) I activity and causes DNA double-strand breaks during DNA replication to induce S phase-dependent cytotoxicity. Here we show that CPT activates NF-kappa B by a mechanism that is dependent on initial nuclear DNA damage followed by cytoplasmic signaling events. NF-kappa B activation by CPT is dramatically diminished in cytoplasts and in CEM/C2 cells expressing a mutant Topo I protein that fails to bind CPT, This response is intensified in S phase cell populations and is prevented by the DNA polymerase inhibitor aphidicolin. In addition, CPT activation of NF-kappa B involves degradation of cytoplasmic I kappa B alpha by the ubiquitin-proteasome pathway in a manner that depends on the I kappa B kinase complex. Finally, inhibition of NF-kappa B activation augments CPT-induced apoptosis, These findings elucidate the progression of signaling events that initiates in the nucleus with CPT-Topo I interaction and continues in the cytoplasm resulting in degradation of I kappa B alpha and nuclear translocation of NF-kappa B to attenuate the apoptotic response.
引用
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页码:9501 / 9509
页数:9
相关论文
共 82 条
[1]   STIMULATION-DEPENDENT I-KAPPA-B-ALPHA PHOSPHORYLATION MARKS THE NF-KAPPA-B INHIBITOR FOR DEGRADATION VIA THE UBIQUITIN-PROTEASOME PATHWAY [J].
ALKALAY, I ;
YARON, A ;
HATZUBAI, A ;
ORIAN, A ;
CIECHANOVER, A ;
BEN-NERIAH, Y .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1995, 92 (23) :10599-10603
[2]   NF-kappa B: Ten years after [J].
Baeuerle, PA ;
Baltimore, D .
CELL, 1996, 87 (01) :13-20
[3]   I-KAPPA-B - A SPECIFIC INHIBITOR OF THE NF-KAPPA-B TRANSCRIPTION FACTOR [J].
BAEUERLE, PA ;
BALTIMORE, D .
SCIENCE, 1988, 242 (4878) :540-546
[4]   The DNA-dependent protein kinase participates in the activation of NFκB following DNA damage [J].
Basu, S ;
Rosenzweig, KR ;
Youmell, M ;
Price, BD .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1998, 247 (01) :79-83
[5]   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
[6]   I-KAPPA-B INTERACTS WITH THE NUCLEAR-LOCALIZATION SEQUENCES OF THE SUBUNITS OF NF-KAPPA-B - A MECHANISM FOR CYTOPLASMIC RETENTION [J].
BEG, AA ;
RUBEN, SM ;
SCHEINMAN, RI ;
HASKILL, S ;
ROSEN, CA ;
BALDWIN, AS .
GENES & DEVELOPMENT, 1992, 6 (10) :1899-1913
[7]   Sequential DNA damage-independent and -dependent activation of NF-κB by UV [J].
Bender, K ;
Göttlicher, M ;
Whiteside, S ;
Rahmsdorf, HJ ;
Herrlich, P .
EMBO JOURNAL, 1998, 17 (17) :5170-5181
[8]  
BROCKMAN JA, 1995, MOL CELL BIOL, V15, P2809
[9]   CENTRAL OF I-KAPPA-B-ALPHA PROTEOLYSIS BY SITE-SPECIFIC, SIGNAL-INDUCED PHOSPHORYLATION [J].
BROWN, K ;
GERSTBERGER, S ;
CARLSON, L ;
FRANZOSO, G ;
SIEBENLIST, U .
SCIENCE, 1995, 267 (5203) :1485-1488
[10]   TARF6 is a signal transducer for interleukin-1 [J].
Cao, ZD ;
Xiong, J ;
Takeuchi, M ;
Kurama, T ;
Goeddel, DV .
NATURE, 1996, 383 (6599) :443-446