Identification of BARD1 as mediator between proapoptotic stress and p53-dependent apoptosis.
The BRCA1-associated protein BARD1 is a putative tumor suppressor. We suggest that BARD1 is a mediator of apoptosis since (1) cell death in vivo (ischemic stroke) and in vitro is accompanied by increased levels of BARD1 protein and mRNA; (2) overexpression of BARD1 induces cell death with all features of apoptosis; and (3) BARD1-repressed cells are defective for the apoptotic response to genotoxic stress. The proapoptotic activity of BARD1 involves binding to and elevations of p53. BRCA1 is not required for but partially counteracts apoptosis induction by BARD1. A tumor-associated mutation Q564H of BARD1 is defective in apoptosis induction, thus suggesting a role of BARD1 in tumor suppression by mediating the signaling from proapoptotic stress toward induction of apoptosis.
Irminger-Finger
I
I
Biology of Aging Laboratory, Department of Geriatrics, Geneva, Switzerland. iirminger@cmu.unige.ch
Leung
W C
WC
Li
J
J
Dubois-Dauphin
M
M
Harb
J
J
Feki
A
A
Jefford
C E
CE
Soriano
J V
JV
Jaconi
M
M
Montesano
R
R
Krause
K H
KH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D004317:Doxorubicin / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D006801:Humans; D002534:Hypoxia, Brain / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020521:Stroke / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D014466:Ultraviolet Rays; D015854:Up-Regulation / Q000187:drug effects / Q000528:radiation effects
D019313:BRCA1 Protein; D002352:Carrier Proteins; D009153:Mutagens; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004317:Doxorubicin; C102449:BARD1 protein, human; C491163:Bard1 protein, mouse; D044767:Ubiquitin-Protein Ligases