title: Proapoptotic BAX and BAK control multiple initiator caspases.
abstract: BAX and BAK operate at both the mitochondria and endoplasmic reticulum (ER) to regulate the intrinsic apoptotic pathway. An unresolved issue is whether any caspases can be activated in response to intrinsic apoptotic signals in the absence of BAX and BAK. Following organelle-specific intrinsic stress signals, including DNA damage and ER stress, we detected no activation of CARD-containing caspases (initiator CASP)-1, -2, -9, -11 and -12 in Bax(-/-)Bak(-/-) doubly deficient (DKO) cells. BCL-2 overexpression in these DKO cells provided no further protection to their already strong protection from DNA damage and ER stress. Moreover, there was no activation of effector CASP-3 and -7 in DKO cells, consistent with the lack of initiator caspase activity and disfavouring a BAX, BAK-independent intrinsic apoptotic pathway to activate initiator caspases. Thus, BAX and BAK confer an essential gateway for the activation of caspases in the intrinsic apoptotic pathway.
authors.affiliation: Howard Hughes Medical Institute, Department of Pathology and Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. aruiz@cnb.uam.es
authors.forename: Antonio
authors.initials: A
authors.lastname: Ruiz-Vela
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Opferman
authors.forename: Emily H-Y
authors.initials: EH
authors.lastname: Cheng
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Korsmeyer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism*; D002458:Cell Fractionation; D002460:Cell Line; D004249:DNA Damage; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D018014:Gene Transfer Techniques; D015151:Immunoblotting; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009841:Oligonucleotides; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034622:RNA Interference; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
chemical_list: C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D008565:Membrane Proteins; D009841:Oligonucleotides; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D020169:Caspases