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Molecular and Cellular Biology, January 2000, p. 575-582, Vol. 20, No. 2
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

c-Jun-Dependent CD95-L Expression Is a Rate-Limiting Step in the Induction of Apoptosis by Alkylating Agents

Andrea Kolbus,1,dagger Ingrid Herr,2 Martin Schreiber,3,Dagger Klaus-Michael Debatin,2 Erwin F. Wagner,3 and Peter Angel1,*

Division of Signal Transduction and Growth Control1 and Division of Pediatric Oncology,2 Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany, and Research Institute of Molecular Pathology (IMP), A-1030 Vienna, Austria3

Received 18 June 1999/Returned for modification 9 August 1999/Accepted 20 October 1999

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.

* Corresponding author. Mailing address: Deutsches Krebsforschungszentrum, Abteilung Signaltransduktion und Wachstumskontrolle, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. Phone: (49)-6221-42-4570. Fax: (49)-6221-42-4554. E-mail: P.angel{at}DKFZ-Heidelberg.de.

dagger Present address: Research Institute of Molecular Pathology (IMP), A-1030 Vienna, Austria.

Dagger Present address: Department of Microbiology and Genetics, Vienna Biocenter, A-1030 Vienna, Austria.

Molecular and Cellular Biology, January 2000, p. 575-582, Vol. 20, No. 2
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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