title: Lessons from gain- and loss-of-function models of pro-survival Bcl2 family proteins: implications for targeted therapy.
abstract: Cell survival depends on the maintenance of mitochondrial integrity controlled by a well-balanced interplay between anti- and pro-apoptotic B cell lymphoma 2 (Bcl2) family members. Given their frequent deregulation in human pathologies, including autoimmunity and cancer, significant research efforts have increased our molecular understanding of how Bcl2 proteins control cell death. This has fostered the development of small non-peptidic compounds, so-called BH3-mimetics, that show excellent prospects of passing clinical trials and entering daily use for targeted therapy. Possible limitations in clinical application may, to a certain degree, be predicted from loss-of-function phenotypes gathered from studies using gene-modified mice that we attempt to summarize and discuss in this context.
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Austria.
authors.forename: Maja
authors.initials: M
authors.lastname: Sochalska
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Austria.
authors.forename: Selma
authors.initials: S
authors.lastname: Tuzlak
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, Third Medical Department, Paracelsus Medical University, Salzburg, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Egle
authors.affiliation: Division of Developmental Immunology, Biocenter, Medical University Innsbruck, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
mesh_terms: D000818:Animals; D002470:Cell Survival; D055786:Gene Knockout Techniques; D006801:Humans; D016393:Lymphoma, B-Cell / Q000378:metabolism / Q000473:pathology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D058990:Molecular Targeted Therapy; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C096816:BCL2-related protein A1; C494811:BCL2L1 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
keywords: Bcl-2 family; apoptosis; cancer; mouse models; targeted therapy