Abstract
Bcl-2 homologues (such as Bcl-x(L)) promote survival in part through sequestration of "activator" BH3-only proteins (such as Puma), preventing them from directly activating Bax. It is thus assumed that inhibition of interactions between activators and Bcl-x(L) is a prerequisite for small molecules to antagonize Bcl-x(L) and induce cell death. The biological properties, described here of a terphenyl-based alpha-helical peptidomimetic inhibitor of Bcl-x(L) attest that displacement of Bax from Bcl-x(L) is also critical. Terphenyl 14 triggers Bax-dependent but Puma-independent cell death, disrupting Bax/Bcl-x(L) interactions without affecting Puma/Bcl-x(L) interactions. In cell-free assays, binding of inactive Bax to Bcl-x(L), followed by its displacement from Bcl-x(L) by terphenyl 14, produces mitochondrially permeabilizing Bax molecules. Moreover, the peptidomimetic kills yeast cells that express Bax and Bcl-x(L), and it uses Bax-binding Bcl-x(L) to induce mammalian cell death. Likewise, ectopic expression of Bax in yeast and mammalian cells enhances sensitivity to another Bcl-x(L) inhibitor, ABT-737, when Bcl-x(L) is present. Thus, the interaction of Bcl-x(L) with Bax paradoxically primes Bax at the same time it keeps Bax activity in check, and displacement of Bax from Bcl-x(L) triggers an apoptotic signal by itself. This mechanism might contribute to the clinical efficiency of Bcl-x(L) inhibitors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Binding Sites
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Biphenyl Compounds / pharmacology
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Cell Death / drug effects
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Cell Death / genetics
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Cell Death / physiology
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Cell Line, Tumor
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Cell-Free System
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Cells, Cultured
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Gene Knockdown Techniques
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HeLa Cells
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Humans
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In Vitro Techniques
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Mice
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Mice, Knockout
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Mitochondria / metabolism
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Models, Biological
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Molecular Mimicry
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Molecular Sequence Data
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Mutation
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Nitrophenols / pharmacology
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Piperazines / pharmacology
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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RNA, Small Interfering / genetics
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Saccharomyces cerevisiae / drug effects
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae / metabolism
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Sulfonamides / pharmacology
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Terphenyl Compounds / pharmacology
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Two-Hybrid System Techniques
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bcl-2-Associated X Protein / deficiency
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism*
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bcl-X Protein / deficiency
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bcl-X Protein / genetics
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bcl-X Protein / metabolism*
Substances
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ABT-737
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Apoptosis Regulatory Proteins
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BAX protein, human
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BBC3 protein, human
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BCL2L1 protein, human
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Bax protein, mouse
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Bcl2l1 protein, mouse
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Biphenyl Compounds
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Nitrophenols
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PUMA protein, mouse
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Piperazines
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Proto-Oncogene Proteins
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RNA, Small Interfering
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Recombinant Proteins
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Sulfonamides
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Terphenyl Compounds
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Tumor Suppressor Proteins
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bcl-2-Associated X Protein
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bcl-X Protein