c-Jun-dependent CD95-L expression is a rate-limiting step in the induction of apoptosis by alkylating agents

被引:140
作者
Kolbus, A
Herr, I
Schreiber, M
Debatin, KM
Wagner, EF
Angel, P
机构
[1] Deutsch Krebsforschungszentrum, Div Signal Transduct & Growth Control, D-69120 Heidelberg, Germany
[2] Deutsch Krebsforschungszentrum, Div Pediat Oncol, D-69120 Heidelberg, Germany
[3] Res Inst Mol Pathol, A-1030 Vienna, Austria
关键词
D O I
10.1128/MCB.20.2.575-582.2000
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
Mouse 3T3 fibroblasts derived from fetuses lacking c-Jun were used to define an essential role of c-Jun, a main component of the transcription factor AP-1, in the cellular response to the alkylating agent methyl methanesulfonate (MMS). MMS represents the most potent and selective activator of the stress-induced kinases JNK/SAPK and p38, resulting in very efficient induction of c-Jun hyperphosphorylation and c-jun transcription. This agent induced apoptosis with high efficiency in wild-type cells but not in c-jun(-/-) cells. Resistance to apoptosis was accompanied by impaired expression of CD95 ligand (CD95-L), a well-known inducer of apoptosis. The addition of recombinant CD95-L restored apoptosis sensitivity in c-jun(-/-) fibroblasts, MMS-induced apoptosis in wild-type fibroblasts or human lymphocytes was strongly reduced by neutralizing CD95-L antibodies or transdominant negative FADD, confirming the importance of CD95 signalling in MMS-induced apoptosis. The loss-of-function approach in fibroblasts allowed the identification and dissection of c-Jun-dependent and -independent processes upstream or downstream of CD95 activation. We have found that c-Jun can act as a proapoptotic regulator in cells exposed to DNA damage via induction of CD95-L. Once activated, CD95-induced death signalling is not affected by the loss of c-Jun, demonstrating that only the initiation and not the execution of stress-induced apoptosis depends on c-Jun.
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页码:575 / 582
页数:8
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