BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly
- PMID: 15721256
- DOI: 10.1016/j.molcel.2005.02.003
BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly
Abstract
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.
Similar articles
-
BH3 domains other than Bim and Bid can directly activate Bax/Bak.J Biol Chem. 2011 Jan 7;286(1):491-501. doi: 10.1074/jbc.M110.167148. Epub 2010 Nov 1. J Biol Chem. 2011. PMID: 21041309 Free PMC article.
-
The BH3 alpha-helical mimic BH3-M6 disrupts Bcl-X(L), Bcl-2, and MCL-1 protein-protein interactions with Bax, Bak, Bad, or Bim and induces apoptosis in a Bax- and Bim-dependent manner.J Biol Chem. 2011 Mar 18;286(11):9382-92. doi: 10.1074/jbc.M110.203638. Epub 2010 Dec 9. J Biol Chem. 2011. PMID: 21148306 Free PMC article.
-
Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies.Nat Cell Biol. 2006 Dec;8(12):1348-58. doi: 10.1038/ncb1499. Epub 2006 Nov 19. Nat Cell Biol. 2006. PMID: 17115033
-
Bax activation by Bim?Cell Death Differ. 2009 Sep;16(9):1187-91. doi: 10.1038/cdd.2009.83. Epub 2009 Jun 26. Cell Death Differ. 2009. PMID: 19557009 Review.
-
Structural biology of the Bcl-2 family of proteins.Biochim Biophys Acta. 2004 Mar 1;1644(2-3):83-94. doi: 10.1016/j.bbamcr.2003.08.012. Biochim Biophys Acta. 2004. PMID: 14996493 Review.
Cited by
-
A novel chromone-based as a potential inhibitor of ULK1 that modulates autophagy and induces apoptosis in colon cancer.Future Med Chem. 2024 Aug 2;16(15):1499-1517. doi: 10.1080/17568919.2024.2363668. Epub 2024 Jul 1. Future Med Chem. 2024. PMID: 38949858
-
Lipid unsaturation promotes BAX and BAK pore activity during apoptosis.Nat Commun. 2024 Jun 3;15(1):4700. doi: 10.1038/s41467-024-49067-6. Nat Commun. 2024. PMID: 38830851 Free PMC article.
-
Directly targeting BAX for drug discovery: Therapeutic opportunities and challenges.Acta Pharm Sin B. 2024 Jun;14(6):2378-2401. doi: 10.1016/j.apsb.2024.02.010. Epub 2024 Feb 10. Acta Pharm Sin B. 2024. PMID: 38828138 Free PMC article. Review.
-
Unlocking the Therapeutic Potential of BCL-2 Associated Protein Family: Exploring BCL-2 Inhibitors in Cancer Therapy.Biomol Ther (Seoul). 2024 May 1;32(3):267-280. doi: 10.4062/biomolther.2023.149. Epub 2024 Apr 9. Biomol Ther (Seoul). 2024. PMID: 38589288 Free PMC article. Review.
-
A novel inhibitory BAK antibody enables assessment of non-activated BAK in cancer cells.Cell Death Differ. 2024 Jun;31(6):711-721. doi: 10.1038/s41418-024-01289-3. Epub 2024 Apr 6. Cell Death Differ. 2024. PMID: 38582955 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials