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J Cell Biol 2007 Apr 23;1772:277-87. doi: 10.1083/jcb.200606065.
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Mitochondrial permeabilization relies on BH3 ligands engaging multiple prosurvival Bcl-2 relatives, not Bak.

Uren RT , Dewson G , Chen L , Coyne SC , Huang DC , Adams JM , Kluck RM .

The Bcl-2 family regulates apoptosis by controlling mitochondrial integrity. To clarify whether its prosurvival members function by sequestering their Bcl-2 homology 3 (BH3)-only ligands or their multidomain relatives Bak and Bax, we analyzed whether four prosurvival proteins differing in their ability to bind specific BH3 peptides or Bak could protect isolated mitochondria. Most BH3 peptides could induce temperature-dependent cytochrome c release, but permeabilization was prevented by Bcl-x(L), Bcl-w, Mcl-1, or BHRF1. However, their protection correlated with the ability to bind Bak rather than the added BH3 peptide and could be overcome only by BH3 peptides that bind directly to the appropriate prosurvival member. Mitochondria protected by both Bcl-x(L)-like and Mcl-1 proteins were disrupted only by BH3 peptides that engage both. BH3-only reagents freed Bak from Bcl-x(L) and Mcl-1 in mitochondrial and cell lysates. The findings support a model for the control of apoptosis in which certain prosurvival proteins sequester Bak/Bax, and BH3-only proteins must neutralize all protective prosurvival proteins to allow Bak/Bax to induce mitochondrial disruption.

PubMed ID: 17452531
PMC ID: PMC2064136
Article link: J Cell Biol
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: bak1 bax bcl2 bcl2l1 bcl2l11 bcl2l2 bid bmf fh mcl1 tbx2

Article Images: [+] show captions
References [+] :
Adams, The Bcl-2 apoptotic switch in cancer development and therapy. 2007, Pubmed