title: Minor cell-death defects but reduced tumor latency in mice lacking the BH3-only proteins Bad and Bmf.
abstract: Proapoptotic Bcl-2 family members of the Bcl-2 homology (BH)3-only subgroup are critical for the establishment and maintenance of tissue homeostasis and can mediate apoptotic cell death in response to developmental cues or exogenously induced forms of cell stress. On the basis of the biochemical experiments as well as genetic studies in mice, the BH3-only proteins Bad and Bmf have been implicated in different proapoptotic events such as those triggered by glucose- or trophic factor-deprivation, glucocorticoids, or histone deacetylase inhibition, as well as suppression of B-cell lymphomagenesis upon aberrant expression of c-Myc. To address possible redundancies in cell death regulation and tumor suppression, we generated compound mutant mice lacking both genes. Our studies revealed lack of redundancy in most paradigms of lymphocyte apoptosis tested in tissue culture. Only spontaneous cell death of thymocytes kept in low glucose or that of pre-B cells deprived of cytokines was significantly delayed when both genes were lacking. Of note, despite these minor apoptosis defects we observed compromised lymphocyte homeostasis in vivo that affected mainly the B-cell lineage. Long-term follow-up revealed significantly reduced latency to spontaneous tumor formation in aged mice when both genes were lacking. Together our study suggests that Bad and Bmf co-regulate lymphocyte homeostasis and limit spontaneous transformation by mechanisms that may not exclusively be linked to the induction of lymphocyte apoptosis.
authors.affiliation: Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: F
authors.initials: F
authors.lastname: Baumgartner
authors.forename: C
authors.initials: C
authors.lastname: Woess
authors.forename: V
authors.initials: V
authors.lastname: Pedit
authors.forename: A
authors.initials: A
authors.lastname: Tzankov
authors.forename: V
authors.initials: V
authors.lastname: Labi
authors.forename: A
authors.initials: A
authors.lastname: Villunger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D016923:Cell Death; D002471:Cell Transformation, Neoplastic; D006410:Hematopoiesis; D006706:Homeostasis; D008214:Lymphocytes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C494820:Bad protein, mouse; C435486:Bmf protein, mouse; D051025:bcl-Associated Death Protein