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

doi:10.1128/MCB.21.11.3684-3691.2001

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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-2family protein Bak prior to the execution phase of apoptosis.Because cisplatin-induced modulation of the related Bax proteinwas seen in only one cell line, a degree of specificity in thesignal to Bak is indicated. Little is known about upstream regulationof Bak activity. In this study, we examined whether the apoptosis-specificpathway mediated by a kinase fragment of MEKK1 ( $Delta$ MEKK1) is involvedin the observed Bak modulation. We report that expression of akinase-inactive fragment of MEKK1 (dominant negative MEKK [dnMEKK])efficiently blocked cisplatin-induced modulation of Bak and cytochromec release and consequently also reduced DEVDase activation andnuclear fragmentation. Accordingly, expression of a kinase-activeMEKK1 fragment (dominant positive MEKK) was sufficient to inducemodulation of Bak in three cell lines and to induce apoptosisin two of these. dnMEKK did not block cisplatin-induced c-JunN-terminal kinase (JNK) activation, in agreement with a specificallyproapoptotic role for the $Delta$ MEKK1 pathway. Finally, we show thatreduction of Bak expression by antisense Bak reduced cisplatin-inducedloss of mitochondrial integrity and caspase cleavage activityin breast cancer cell lines. In summary, we have identified Bakas a cisplatin-regulated component downstream in a proapoptotic,JNK-independent $Delta$ MEKK1pathway.

^* Corresponding author. Mailing address: Radiumhemmet's Research Laboratory, Cancer Center Karolinska, Department of Oncology-Pathology,Karolinska Institute, S-171 76 Stockholm, Sweden. Phone: 46 851 77 54 60. Fax: 46 8 33 90 31. E-mail: mimmi.shoshan{at}onkpat.ki.se.

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

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