Journal
MOLECULAR CELL
Volume 17, Issue 4, Pages 525-535Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2005.02.003
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Funding
- NCI NIH HHS [CA69381] Funding Source: Medline
- NIAID NIH HHS [AI40646] Funding Source: Medline
- NIA NIH HHS [R21AG024157] Funding Source: Medline
- NIGMS NIH HHS [GM62289, GM50284] Funding Source: Medline
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Using a Bax-dependent membrane-permeabilization assay, we show that peptides corresponding to the BH3 domains of Bcl-2 family BH3-only proteins have dual functions. Several BH3 peptides relieved the inhibition of Bax caused by the antiapoptotic Bcl-X-L and/or Mcl-1 proteins, some displaying a specificity for either Bcl-X-L or Mcl-1. Besides having this derepression function, the Bid and Bim peptides activated Bax directly and were the only BH3 peptides tested that could potently induce cytochrome c release from mitochondria in cultured cells. Furthermore, Bax activator molecules (cleaved Bid protein and the Bim BH3 peptide) synergistically induced cytochrome c release when introduced into cells along with derepressor BH3 peptides. These observations support a unified model of BH3 domain function, encompassing both positive and negative regulation of other Bcl-2 family members. In this model, the simple inhibition of antiapoptotic functions is insufficient to induce apoptosis unless a direct activator of Bax or Bak is present.
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