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

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Item Type:Article
Title:Mcl-1 determines the Bax dependency of Nbk/Bik-induced apoptosis
Creators Name:Gillissen, B. and Essmann, F. and Hemmati, P.G. and Richter, A. and Richter, A. and Oztop, I. and Chinnadurai, G. and Doerken, B. and Daniel, P.T.
Abstract: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.
Keywords:Adenoviridae, Apoptosis, Apoptosis Regulatory Proteins, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, Benzimidazoles, Biological Models, Carbocyanines, Cell Line, Cell Membrane Permeability, Cytochromes C, Fluorescent Dyes, HCT116 Cells, Kidney, Membrane Proteins, Mitochondria, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Proteins, Prostatic Neoplasms, Proto-Oncogene Proteins c-bcl-2, Transgenes, Tumor Cell Line
Source:Journal of Cell Biology
Publisher:Rockefeller University Press
Page Range:701-715
Date:19 November 2007
Official Publication:https://doi.org/10.1083/jcb.200703040
PubMed:View item in PubMed

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