title: Bax activation by engagement with, then release from, the BH3 binding site of Bcl-xL.
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.
authors.affiliation: Centre de Recherche en Cancérologie Nantes Angers-UMR 892-INSERM/Université de Nantes, Institut de Recherche Thérapeutique de l'Université de Nantes, Nantes, France.
authors.forename: F
authors.initials: F
authors.lastname: Gautier
authors.forename: Y
authors.initials: Y
authors.lastname: Guillemin
authors.forename: P F
authors.initials: PF
authors.lastname: Cartron
authors.forename: T
authors.initials: T
authors.lastname: Gallenne
authors.forename: N
authors.initials: N
authors.lastname: Cauquil
authors.forename: T
authors.initials: T
authors.lastname: Le Diguarher
authors.forename: P
authors.initials: P
authors.lastname: Casara
authors.forename: F M
authors.initials: FM
authors.lastname: Vallette
authors.forename: S
authors.initials: S
authors.lastname: Manon
authors.forename: J A
authors.initials: JA
authors.lastname: Hickman
authors.forename: O
authors.initials: O
authors.lastname: Geneste
authors.forename: P
authors.initials: P
authors.lastname: Juin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D002474:Cell-Free System; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009154:Mutation; D009596:Nitrophenols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013730:Terphenyl Compounds / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D020798:Two-Hybrid System Techniques; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C501332:ABT-737; D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C438378:BBC3 protein, human; C494811:BCL2L1 protein, human; C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D001713:Biphenyl Compounds; D009596:Nitrophenols; C488588:PUMA protein, mouse; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D013449:Sulfonamides; D013730:Terphenyl Compounds; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein