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p14ARF-induced Apoptosis in p53 Protein-deficient Cells Is Mediated by BH3-only Protein-independent Derepression of Bak Protein through Down-regulation of Mcl-1 and Bcl-xL Proteins.

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Title: p14ARF-induced Apoptosis in p53 Protein-deficient Cells Is Mediated by BH3-only Protein-independent Derepression of Bak Protein through Down-regulation of Mcl-1 and Bcl-xL Proteins.
Authors: Müer, Annika1,2, Overkamp, Tim1,2, Gillissen, Bernd1,2, Richter, Antje1,2, Pretzsch, Thomas3, Milojkovic, Ana1,2, Dörken, Bernd1,2,3, Daniel, Peter T.1,2,3 pdaniel@mdc-berlin.de, Hemmati, Philipp1,2,3
Source: Journal of Biological Chemistry. 5/18/2012, Vol. 287 Issue 21, p17343-17352. 10p.
Subjects: Tumor suppressor proteins, Cell cycle, Apoptosis, Permeability (Biology), DNA
Abstract: The p14ARF tumor suppressor plays a central role in regulating cell cycle arrest and apoptosis. We reported previously that p14ARF is capable of triggering apoptosis in a p53-independent manner. However, the mechanism remained 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. Although forced expression of Bak markedly sensitizes toward p14ARF-induced apoptosis, re-expression of Bax has no effect. Vice versa, knockdown 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 overexpression 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. [ABSTRACT FROM AUTHOR]
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Database: Engineering Source
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Abstract:The p14ARF tumor suppressor plays a central role in regulating cell cycle arrest and apoptosis. We reported previously that p14ARF is capable of triggering apoptosis in a p53-independent manner. However, the mechanism remained 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. Although forced expression of Bak markedly sensitizes toward p14ARF-induced apoptosis, re-expression of Bax has no effect. Vice versa, knockdown 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 overexpression 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. [ABSTRACT FROM AUTHOR]
ISSN:00219258
DOI:10.1074/jbc.M111.314898