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p14ARF-induced apoptosis in p53-deficient cells is mediated by the BH3-only protein independent de-repression of Bak through down-regulation of Mcl-1 and Bcl-xL

Item Type:Article
Title:p14ARF-induced apoptosis in p53-deficient cells is mediated by the BH3-only protein independent de-repression of Bak through down-regulation of Mcl-1 and Bcl-xL
Creators Name:Muer, A. and Overkamp, T. and Gillissen, B. and Richter, A. and Pretzsch, T. and Milojkovic, A. and Doerken, B. and Daniel, P.T. and Hemmati, P.
Abstract:The p14ARF tumor suppressor plays a central role in regulating cell cycle arrest and apoptosis. We previously reported that p14ARF is capable of triggering apoptosis in a p53-independent manner. The mechanism remained, however, unclear. Here, we demonstrate that the p53-independent activation of the mitochondrial apoptosis pathway by p14ARF is primarily mediated by the pro-apoptotic Bax-homolog Bak. Expression of p14ARF exclusively triggers a N-terminal conformational switch of Bak, but not Bax, which allows for mitochondrial permeability shift, release of cytochrome c, activation of caspases, and subsequent fragmentation of genomic DNA. Whereas forced expression of Bak markedly sensitizes towards p14ARF-induced apoptosis, re-expression of Bax has no effect. Vice versa, knock-down of Bak by RNA interference attenuates p14ARF-induced apoptosis, whereas down-regulation of Bax has no effect. Bak activation coincides with a prominent, caspase-independent deprivation of the endogenous Bak inhibitors Mcl-1 and Bcl-xL. In turn, mitochondrial apoptosis is fully blocked by over-expression of either Mcl-1 or Bcl-xL. Taken together, these data indicate that in the absence of functional p53 and Bax, p14ARF triggers mitochondrial apoptosis signaling by activating Bak, which is facilitated by down-regulating anti-apoptotic Mcl-1 and Bcl-xL. Moreover, our data suggest that the simultaneous inhibition of two central endogenous Bak inhibitors, i.e. Mcl-1 and Bcl-xL, may be sufficient to activate mitochondrial apoptosis in the absence of BH3-only protein regulation.
Keywords:Apoptosis, ARF, Bax, Bcl-2 Family Proteins, Mitochondrial Apoptosis, BH3-only Proteins, Bcl-xL, Mcl-1
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology (U.S.A.)
Volume:287
Number:21
Page Range:17343-17352
Date:18 May 2012
Official Publication:https://doi.org/10.1074/jbc.M111.314898
PubMed:View item in PubMed

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