Hsp27 functions as a negative regulator of cytochrome c-dependent activation of procaspase-3

被引:238
作者
Pandey, P
Farber, R
Nakazawa, A
Kumar, S
Bharti, A
Nalin, C
Weichselbaum, R
Kufe, D
Kharbanda, S
机构
[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA
[2] Novartis Pharmaceut, E Hanover, NJ 07936 USA
[3] Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA
关键词
Hsp27; cytochrome c; caspase-3; apoptosis;
D O I
10.1038/sj.onc.1203531
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
The release of mitochondrial cytochrome c by genotoxic stress induces the formation of a cytosolic complex with Apaf-1 (mammalian CED4 homolog) and thereby the activation of procaspase-3 (cas-3) and procaspase-9 (cas-9). Here we demonstrate that heat-shock protein 27 (Hsp27) inhibits cytochrome c (cyt c)-dependent activation of cas-3. Hsp27 had no effect on cyt c release, Apaf-1 and cas-9 activation. By contrast, our results show that Hsp27 associates with cas-3, but not Apaf-1 or cas-9, and inhibits activation of cas-3 by cas-9-mediated proteolysis, Furthermore, the present results demonstrate that immunodepletion of Hsp27 depletes cas-3, Importantly, treatment of cells with DNA damaging agents dissociates the Hsp27/cas-3 complex and relieves inhibition of cas-3 activation. These findings define a novel function for Hsp27 and provide the first evidence that a heat shock protein represses cas-3 activation.
引用
收藏
页码:1975 / 1981
页数:7
相关论文
共 47 条
[1]   Human ICE/CED-3 protease nomenclature [J].
Alnemri, ES ;
Livingston, DJ ;
Nicholson, DW ;
Salvesen, G ;
Thornberry, NA ;
Wong, WW ;
Yuan, JY .
CELL, 1996, 87 (02) :171-171
[2]   DYNAMIC CHANGES IN THE STRUCTURE AND INTRACELLULAR LOCALE OF THE MAMMALIAN LOW-MOLECULAR-WEIGHT HEAT-SHOCK PROTEIN [J].
ARRIGO, AP ;
SUHAN, JP ;
WELCH, WJ .
MOLECULAR AND CELLULAR BIOLOGY, 1988, 8 (12) :5059-5071
[3]  
ARRIGO AP, 1994, HEAT SHOCK PROTEINS, P335
[4]  
Chaufour S, 1996, CELL STRESS CHAPERON, V1, P225, DOI 10.1379/1466-1268(1996)001<0225:TAPACI>2.3.CO
[5]  
2
[6]   Caspases: the executioners of apoptosis [J].
Cohen, GM .
BIOCHEMICAL JOURNAL, 1997, 326 :1-16
[7]   Proteolytic activation of protein kinase C delta by an ICE-like protease in apoptotic cells [J].
Emoto, Y ;
Manome, Y ;
Meinhardt, G ;
Kisaki, H ;
Kharbanda, S ;
Robertson, M ;
Ghayur, T ;
Wong, WW ;
Kamen, R ;
Weichselbaum, R ;
Kufe, D .
EMBO JOURNAL, 1995, 14 (24) :6148-6156
[8]   INHIBITION OF THE DIFFERENTIATION OF HUMAN MYELOID CELL-LINES BY REDOX CHANGES INDUCED THROUGH GLUTATHIONE DEPLETION [J].
ESPOSITO, F ;
AGOSTI, V ;
MORRONE, G ;
MORRA, F ;
CUOMO, C ;
RUSSO, T ;
VENUTA, S ;
CIMINO, F .
BIOCHEMICAL JOURNAL, 1994, 301 :649-653
[9]   Proteolytic activation of protein kinase C delta by an ICE/CED 3-like protease induces characteristics of apoptosis [J].
Ghayur, T ;
Hugunin, M ;
Talanian, RV ;
Ratnofsky, S ;
Quinlan, C ;
Emoto, Y ;
Pandey, P ;
Datta, R ;
Huang, YY ;
Kharbanda, S ;
Allen, H ;
Kamen, R ;
Wong, W ;
Kufe, D .
JOURNAL OF EXPERIMENTAL MEDICINE, 1996, 184 (06) :2399-2404
[10]   C-ELEGANS CELL-SURVIVAL GENE CED-9 ENCODES A FUNCTIONAL HOMOLOG OF THE MAMMALIAN PROTOONCOGENE BCL-2 [J].
HENGARTNER, MO ;
HORVITZ, HR .
CELL, 1994, 76 (04) :665-676