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- Title
Mcl-1 determines the Bax dependency of Nbk/Bik-induced apoptosis.
- Authors
Gillissen, Bernhard; Essmann, Frank; Hemmati, Philipp G.; Richter, Antje; Richter, Anja; Öztop, Ilker; Chinnadurai, Govindaswamy; Dörken, Bernd; Daniel, Peter 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.
- Subjects
B cell lymphoma; HOMOLOGY (Biology); CELL death; APOPTOSIS; ANTINEOPLASTIC agents
- Publication
Journal of Cell Biology, 2007, Vol 179, Issue 4, p701
- ISSN
0021-9525
- Publication type
Article
- DOI
10.1083/jcb.200703040