Cisplatin induces the proapoptotic conformation of Bak in a ΔMEKK1-dependent manner

Aleksandra Mandic, Kristina Viktorsson, Magnus Molin, GÖRAN Akusjärvi, Hidetaka Eguchi, Shin Ichi Hayashi, Masakazu Toi, Johan Hansson, Stig Linder, Maria C. Shoshan

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69 Citations (Scopus)

Abstract

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 (ΔMEKK1) 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 ΔMEKK1 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 ΔMEKK1 pathway.

Original languageEnglish
Pages (from-to)3684-3691
Number of pages8
JournalMolecular and cellular biology
Volume21
Issue number11
DOIs
Publication statusPublished - 2001 Jun
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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