title: BAD is a pro-survival factor prior to activation of its pro-apoptotic function.
abstract: The mammalian BAD protein belongs to the BH3-only subgroup of the BCL-2 family. In contrast to its known pro-apoptotic function, we found that endogenous and overexpressed BAD(L) can inhibit cell death in neurons and other cell types. Several mechanisms regulate the conversion of BAD from an anti-death to a pro-death factor, including alternative splicing that produces the N-terminally truncated BAD(S). In addition, caspases convert BAD(L) into a pro-death fragment that resembles the short splice variant. The caspase site that is selectively cleaved during cell death following growth factor (interleukin-3) withdrawal is conserved between human and murine BAD. A second cleavage site that is required for murine BAD to promote death following Sindbis virus infection, gamma-irradiation, and staurosporine treatment is not conserved in human BAD, consistent with the inability of human BAD to promote death with these stimuli. However, loss of the BAD N terminus by any mechanism is not always sufficient to activate its pro-death activity, suggesting that the N terminus is a regulatory domain rather than an anti-death domain. These findings suggest that BAD is more than an inert death factor in healthy cells; it is also a pro-survival factor, prior to its role in promoting cell death.
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD21205, USA.
authors.forename: So Young
authors.initials: SY
authors.lastname: Seo
authors.forename: Ying-Bei
authors.initials: YB
authors.lastname: Chen
authors.forename: Iva
authors.initials: I
authors.lastname: Ivanovska
authors.forename: Ann M
authors.initials: AM
authors.lastname: Ranger
authors.forename: Suk J
authors.initials: SJ
authors.lastname: Hong
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Korsmeyer
authors.forename: David S
authors.initials: DS
authors.lastname: Bellows
authors.forename: Yihru
authors.initials: Y
authors.lastname: Fannjiang
authors.forename: J Marie
authors.initials: JM
authors.lastname: Hardwick
mesh_terms: D018354:Alphavirus Infections / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival; D017124:Conserved Sequence; D005720:Gamma Rays / Q000009:adverse effects; D006801:Humans; D051379:Mice; D009474:Neurons / Q000166:cytology*; D012845:Sindbis Virus; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection; D051025:bcl-Associated Death Protein
chemical_list: C494819:BAD protein, human; C494820:Bad protein, mouse; D002352:Carrier Proteins; D051025:bcl-Associated Death Protein; D020169:Caspases; D019311:Staurosporine