Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics.
By A. Letai, Michael C. Bassik, L. Walensky, M. Sorcinelli, S. Weiler, S. Korsmeyer. Cancer Cell, 2002
1,714 citations recorded by the source corpus.
The "BH3-only" proteins of the BCL-2 family require "multidomain" proapoptotic members BAX and BAK to release cytochrome c from mitochondria and kill cells. We find short peptides representing the alpha-helical BH3 domains of BID or BIM are capable of inducing oligomerization of BAK and BAX to release cytochrome c. Another subset characterized by the BH3 peptides from BAD and BIK cannot directly activate BAX, BAK but instead binds antiapoptotic BCL-2, resulting in the displacement of BID-like BH3 domains that initiate mitochondrial dysfunction. Transduced BAD-like and BID-like BH3 peptides also displayed synergy in killing leukemic cells. These data support a two-class model for BH3 domains: BID-like domains that "activate" BAX, BAK and BAD-like domains that "sensitize" by occupying the pocket of antiapoptotic members.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/7c1269886fc7e97540965be9bce02cee0b9cce1e
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In Molecular Biology
- Guido Kroemer
- Douglas R. Green
- Jerry M. Adams
- L. Galluzzi
- Simone Fulda
- A. Letai
- Beth Levine
- Suzanne Cory
Citations in the corpus
- Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. (2005, background): “As discussed elsewhere (Adams 2003), one of several plausible models for the initiation of cell death posits that, once BH3-only proteins have overwhelmed their prosurvival relatives, certain BH3-only proteins then directly bind Bax or Bak to initiate their activation (Kuwana et al. 2002; Letai et a”
- Tumor resistance to apoptosis (2009, background): “, Bad, bind to the pro-survival Bcl-2 proteins.(51) According to the indirect acti-”
- Functional and physical interaction between Bcl‐XL and a BH3‐like domain in Beclin‐1 (2007, background): “…crosstalk between autophagy and apoptosis is mediated at least in part by the functional and physical interaction between Beclin-1, an essential autophagy gene, and Bcl-2, one of the paradigmatic apoptosis-inhibitory pro- teins (Liang et al, 1999; Pattingre et al, 2005; Takacs-Vellai et al, 2005).”
- Apoptosis: controlled demolition at the cellular level (2008, background): “BAX (BCL-2-associated X protein) and/or BAK (BCL-2-antagonist/killer-1) become activated early in apoptosis through the actions of one or more BH3-only proteins , and this results in permeabilization of mitochondrial outer membranes and release of mitochondrial intermembrane space protein”