title: Antiapoptotic potency of Bcl-2 proteins primarily relies on their stability, not binding selectivity.
abstract: All 6 human prosurvival Bcl-2 proteins can drive cancer development and contribute to therapy resistance. However, their relative abilities to protect cells against cancer therapy were not examined previously. We report that Bcl-2, Bcl-xL, or Bcl-w consistently protected leukemic cells better than Bcl-B, Bfl-1, or Mcl-1 against a wide variety of anticancer regimens. Current thinking would attribute this to differences in their ability to bind to BH3-only proteins, Bax, and Bak. To address this, we established the first complete, quantitative cellular interaction profile of all human prosurvival Bcl-2 proteins with all their proapoptotic relatives. Binding was unexpectedly promiscuous, except for Bad and Noxa, and did not explain the differential antiapoptotic capacity of the Bcl-2 proteins. Rather, Bcl-B, Bfl-1, or Mcl-1 proved less potent due to steady-state or drug-induced proteasomal degradation. All 6 Bcl-2 proteins similarly protected against the diverse anticancer regimens when expressed at equal protein levels, in agreement with their broad interaction profile. Therefore, clinical diagnostics should include all family members and should be performed at the protein rather than at the messenger RNA level. In drug development, targeting the ubiquitination machinery of prosurvival Bcl-2 proteins will complement and potentially improve on targeting Bcl-2 protein interactions with BH3 mimetics.
authors.affiliation: Division of Immunology and.
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Rooswinkel
authors.forename: Bert
authors.initials: B
authors.lastname: van de Kooij
authors.forename: Evert
authors.initials: E
authors.lastname: de Vries
authors.forename: Madelon
authors.initials: M
authors.lastname: Paauwe
authors.forename: Rens
authors.initials: R
authors.lastname: Braster
authors.forename: Marcel
authors.initials: M
authors.lastname: Verheij
authors.forename: Jannie
authors.initials: J
authors.lastname: Borst
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D055550:Protein Stability; D059748:Proteolysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C117144:BCL2-like 10 protein; C096816:BCL2-related protein A1; C491073:BCL2L2 protein, human; C579095:MCL1 protein, human; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein