BAD is a pro-survival factor prior to activation of its pro-apoptotic function.
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.
Seo
So Young
SY
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD21205, USA.
Chen
Ying-Bei
YB
Ivanovska
Iva
I
Ranger
Ann M
AM
Hong
Suk J
SJ
Dawson
Valina L
VL
Korsmeyer
Stanley J
SJ
Bellows
David S
DS
Fannjiang
Yihru
Y
Hardwick
J Marie
JM
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
C494819:BAD protein, human; C494820:Bad protein, mouse; D002352:Carrier Proteins; D051025:bcl-Associated Death Protein; D020169:Caspases; D019311:Staurosporine