title: Caspase cleavage enhances the apoptosis-inducing effects of BAD.
abstract: The function of BAD, a proapoptotic member of the Bcl-2 family, is regulated primarily by rapid changes in phosphorylation that modulate its protein-protein interactions and subcellular localization. We show here that, during interleukin-3 (IL-3) deprivation-induced apoptosis of 32Dcl3 murine myeloid precursor cells, BAD is cleaved by a caspase(s) at its N terminus to generate a 15-kDa truncated protein. The 15-kDa truncated BAD is a more potent inducer of apoptosis than the wild-type protein, whereas a mutant BAD resistant to caspase 3 cleavage is a weak apoptosis inducer. Truncated BAD is detectable only in the mitochondrial fraction, interacts with BCL-X(L) at least as effectively as the wild-type protein, and is more potent than wild-type BAD in inducing cytochrome c release. Human BAD, which is 43 amino acids shorter than its mouse counterpart, is also cleaved by a caspase(s) upon exposure of Jurkat T cells to anti-FAS antibody, tumor necrosis factor alpha (TNF-alpha), or TRAIL. Moreover, a truncated form of human BAD lacking the N-terminal 28 amino acids is more potent than wild-type BAD in inducing apoptosis. The generation of truncated BAD was blocked by Bcl-2 in IL-3-deprived 32Dcl3 cells but not in Jurkat T cells exposed to anti-FAS antibody, TNF-alpha, or TRAIL. Together, these findings point to a novel and important role for BAD in maintaining the apoptotic phenotype in response to various apoptosis inducers.
authors: Department of Microbiology/Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors: F
authors: F
authors: Condorelli
authors: P
authors: P
authors: Salomoni
authors: S
authors: S
authors: Cotteret
authors: V
authors: V
authors: Cesi
authors: S M
authors: SM
authors: Srinivasula
authors: E S
authors: ES
authors: Alnemri
authors: B
authors: B
authors: Calabretta
mesh_terms: D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism* / Q000502:physiology; D002470:Cell Survival; D003470:Culture Media; D003574:Cytochrome c Group / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D013347:Subcellular Fractions; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
chemical_list: C494819:BAD protein, human; C494811:BCL2L1 protein, human; C494820:Bad protein, mouse; C494812:Bcl2l1 protein, mouse; D002352:Carrier Proteins; D003470:Culture Media; D003574:Cytochrome c Group; D007377:Interleukin-3; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases