Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death.
Multiple death signals influence mitochondria during apoptosis, yet the critical initiating event for mitochondrial dysfunction in vivo has been unclear. tBID, the caspase-activated form of a "BH3-domain-only" BCL-2 family member, triggers the homooligomerization of "multidomain" conserved proapoptotic family members BAK or BAX, resulting in the release of cytochrome c from mitochondria. We find that cells lacking both Bax and Bak, but not cells lacking only one of these components, are completely resistant to tBID-induced cytochrome c release and apoptosis. Moreover, doubly deficient cells are resistant to multiple apoptotic stimuli that act through disruption of mitochondrial function: staurosporine, ultraviolet radiation, growth factor deprivation, etoposide, and the endoplasmic reticulum stress stimuli thapsigargin and tunicamycin. Thus, activation of a "multidomain" proapoptotic member, BAX or BAK, appears to be an essential gateway to mitochondrial dysfunction required for cell death in response to diverse stimuli.
Wei
M C
MC
Howard Hughes Medical Institute, Departments of Pathology and Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Zong
W X
WX
Cheng
E H
EH
Lindsten
T
T
Panoutsakopoulou
V
V
Ross
A J
AJ
Roth
K A
KA
MacGregor
G R
GR
Thompson
C B
CB
Korsmeyer
S J
SJ
D000818:Animals; D000906:Antibodies; D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein; D001704:Biopolymers; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology; D014162:Transfection; D014466:Ultraviolet Rays; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000276:immunology / Q000502:physiology
D000906:Antibodies; D051023:BH3 Interacting Domain Death Agonist Protein; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; C494815:Bid protein, mouse; D001704:Biopolymers; D002352:Carrier Proteins; D003574:Cytochrome c Group; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D005047:Etoposide; D019311:Staurosporine