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Molecular and Cellular Biology, June 2001, p. 3684-3691, Vol. 21, No. 11
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.11.3684-3691.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Cisplatin Induces the Proapoptotic Conformation of Bak in a Delta MEKK1-Dependent Manner

Aleksandra Mandic,1 Kristina Viktorsson,1 Magnus Molin,2 Göran Akusjärvi,2 Hidetaka Eguchi,3 Shin-Ichi Hayashi,3 Masakazu Toi,4 Johan Hansson,1 Stig Linder,1 and Maria C. Shoshan1,*

Radiumhemmet's Research Laboratory, Cancer Center Karolinska, Department of Oncology-Pathology, Karolinska Institute, S-171 76 Stockholm,1 and Department of Medical Biochemistry and Microbiology, BMC, Uppsala University, S-751 23 Uppsala,2 Sweden, and Saitama Cancer Center Research Institute, Kita-adachigun, Saitama 362-0806,3 and Tokyo Metropolitan Hospital, Bunkyo-ku, Tokyo,4 Japan

Received 20 September 2000/Returned for modification 29 November 2000/Accepted 22 February 2001

In a panel of four human melanoma cell lines, equitoxic doses of cisplatin induced the proapoptotic conformation of the Bcl-2 family protein Bak prior to the execution phase of apoptosis. Because cisplatin-induced modulation of the related Bax protein was seen in only one cell line, a degree of specificity in the signal to Bak is indicated. Little is known about upstream regulation of Bak activity. In this study, we examined whether the apoptosis-specific pathway mediated by a kinase fragment of MEKK1 (Delta MEKK1) is involved in the observed Bak modulation. We report that expression of a kinase-inactive fragment of MEKK1 (dominant negative MEKK [dnMEKK]) efficiently blocked cisplatin-induced modulation of Bak and cytochrome c release and consequently also reduced DEVDase activation and nuclear fragmentation. Accordingly, expression of a kinase-active MEKK1 fragment (dominant positive MEKK) was sufficient to induce modulation of Bak in three cell lines and to induce apoptosis in two of these. dnMEKK did not block cisplatin-induced c-Jun N-terminal kinase (JNK) activation, in agreement with a specifically proapoptotic role for the Delta MEKK1 pathway. Finally, we show that reduction of Bak expression by antisense Bak reduced cisplatin-induced loss of mitochondrial integrity and caspase cleavage activity in breast cancer cell lines. In summary, we have identified Bak as a cisplatin-regulated component downstream in a proapoptotic, JNK-independent Delta MEKK1 pathway.

* Corresponding author. Mailing address: Radiumhemmet's Research Laboratory, Cancer Center Karolinska, Department of Oncology-Pathology, Karolinska Institute, S-171 76 Stockholm, Sweden. Phone: 46 8 51 77 54 60. Fax: 46 8 33 90 31. E-mail: mimmi.shoshan{at}onkpat.ki.se.

Molecular and Cellular Biology, June 2001, p. 3684-3691, Vol. 21, No. 11
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.11.3684-3691.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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