Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members.

By Michael T. Certo, Victoria Del Gaizo Moore, Mari Nishino, G. Wei, S. Korsmeyer, Scott A. Armstrong, A. Letai. Cancer Cell, 2006

1,299 citations recorded by the source corpus.

We show that the antiapoptotic proteins BCL-2, BCL-XL, MCL-1, BFL-1, and BCL-w each bear a unique pattern of interaction with a panel of peptides derived from BH3 domains of BH3-only proteins. Cellular dependence on an antiapoptotic protein for survival can be decoded based on the pattern of mitochondrial sensitivity to this peptide panel, a strategy that we call BH3 profiling. Dependence on antiapoptotic proteins correlates with sequestration of activator BH3-only proteins like BID or BIM by antiapoptotic proteins. Sensitivity to the cell-permeable BCL-2 antagonist ABT-737 is also related to priming of BCL-2 by activator BH3-only molecules. Our data allow us to distinguish a cellular state we call "primed for death," which can be determined by BH3 profiling and which correlates with dependence on antiapoptotic family members for survival.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a5bc54566cafc045b4c07fc165bb08814302d590

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In Molecular Biology

1. Jerry M. Adams
2. Douglas R. Green
3. Suzanne Cory
4. A. Letai
5. J. Chipuk
6. F. Llambi
7. Guido Kroemer
8. S. Tait

Citations in the corpus

• Control of mitochondrial apoptosis by the Bcl-2 family (2009, methodology): “Each anti-apoptotic protein has its own pattern of interaction with sensitizer proteins (Certo et al., 2006; Chen et al., 2005; Kuwana et al., 2005; Opferman et al., 2003).”
• Hypoxia-Induced Autophagy Is Mediated through Hypoxia-Inducible Factor Induction of BNIP3 and BNIP3L via Their BH3 Domains (2009, background): “This association is of low affinity (1 to 2 M range) (23), and one could imagine that the BH3 domains of BNIP3 and BNIP3L, which have atypical features (6), easily could compete with Beclin1 and promote autophagy, whereas they fail to induce apoptosis because of their low affinity for Bcl-2, Bcl-XL,”
• BCL-2 family antagonists for cancer therapy (2008, background): “Alternatively, some data support a direct interaction between certain BH3-only proteins and BA”
• BCL-2 family proteins: changing partners in the dance towards death (2017, background): “subsequent apoptosis.(104) Inactivating the anti-apoptotic BCL-2 family proteins with small molecule BH3 mimetic drugs is one potential ‘push’ as displacing the active but sequestered pro-apoptotic proteins results in MOMP.”
• Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy (2015, neutral): “After this incubation, we permeabilize, stain with the fluorescent dye JC-1 and expose the cells to different BH3 peptides that will promote mitochondrial depolarization and MOMP, the ultimate event that triggers apoptosis.”
• ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. (2008, background): “In contrast to nonmalignant cells, cancer cells are continually bombarded by multiple stress signals that predispose them to die (1, 25).”
• Caspase functions in cell death and disease. (2013, background): “certain caspase activators, such as those that inhibit antiapoptotic molecules like Bcl-2, appear to have an enhanced therapeutic index when used to treat cancer cells that rely mainly on antiapoptotic proteins to stave off cell death (Certo et al. 2006).”
• The BCL-2 Family Reunion (2010, background): “Derepression also represents a means of pharmacological regulation incertain tumors, suchaschronic lymphocytic leukemia (CLL), which undergo MOMP when treated with a derepressor BH3 mimetic (Certo et al., 2006; Del Gaizo Moore et al., 2007).”
• How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? (2008, positive): “This also highlights the sensitizer function of BH3-only proteins, which is possiblewithanyBH3-onlypeptideor,intheory,protein.In this situation, BH3-only proteins inhibit cellular anti-apoptotic proteins, and any further direct activator BH3-only activity is free to induce MOMP (Figure 3d) [18, 19 ,”
• Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. (2006, background): “These findings also do not support the recently proposed model of cell death that implies requirements of ‘‘stress’’ to engage the direct activators of BAX and BAK (i.e., BIM or tBID) in cells that are ‘‘addicted’’ to the antiapoptotic BCL-2 proteins (Certo et al., 2006).”