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Published online November 19, 2007
doi:10.1083/jcb.200703040
The Journal of Cell Biology, Vol. 179, No. 4, 701-715
The Rockefeller University Press, 0021-9525 $30.00
© 2007 Gillissen et al.
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Article

Mcl-1 determines the Bax dependency of Nbk/Bik-induced apoptosis



Bernhard Gillissen1, Frank Essmann3, Philipp G. Hemmati1, Antje Richter1, Anja Richter1, Ilker Öztop1, Govindaswamy Chinnadurai4, Bernd Dörken1,2, and Peter T. Daniel1,2

1 Department of Hematology, Oncology, and Tumor Immunology, University Medical Center Charité, 13125 Berlin, Germany
2 Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany
3 Institute of Molecular Medicine, Heinrich Heine University, 40225 Düsseldorf, Germany
4 Institute for Molecular Virology, Saint Louis University School of Medicine, St. Louis, MO 63110

Correspondence to Peter Daniel: pdaniel{at}mdc-berlin.de

B cell lymphoma 2 (Bcl-2) homology domain 3 (BH3)–only proteins of the Bcl-2 family are important functional adaptors that link cell death signals to the activation of Bax and/or Bak. The BH3-only protein Nbk/Bik induces cell death via an entirely Bax-dependent/Bak-independent mechanism. In contrast, cell death induced by the short splice variant of Bcl-x depends on Bak but not Bax. This indicates that Bak is functional but fails to become activated by Nbk. Here, we show that binding of myeloid cell leukemia 1 (Mcl-1) to Bak persists after Nbk expression and inhibits Nbk-induced apoptosis in Bax-deficient cells. In contrast, the BH3-only protein Puma disrupts Mcl-1–Bak interaction and triggers cell death via both Bax and Bak. Targeted knockdown of Mcl-1 overcomes inhibition of Bak and allows for Bak activation by Nbk. Thus, Nbk is held in check by Mcl-1 that interferes with activation of Bak. The finding that different BH3-only proteins rely specifically on Bax, Bak, or both has important implications for the design of anticancer drugs targeting Bcl-2.

Abbreviations used in this paper: Bcl, B cell lymphoma; BH, Bcl-2 homology; CMV, cytomegalovirus; Mcl, myeloid cell leukemia; PI, propidium iodide; wt, wild type.


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