Bim and Noxa are candidates to mediate the deleterious effect of the NF-kappa B subunit RelA in cerebral ischemia.
The transcription factor nuclear factor kappaB (NF-kappaB) is well known for its antiapoptotic action. However, in some disorders, such as cerebral ischemia, a proapoptotic function of NF-kappaB has been demonstrated. To analyze which subunit of NF-kappaB is functional in cerebral ischemia, we induced focal cerebral ischemia in mice with a germline deletion of the p52 or c-Rel gene or with a conditional deletion of RelA in the brain. Only RelA deficiency reduced infarct size. Interestingly, expression of the proapoptotic BH3 (Bcl-2 homology domain 3)-only genes Bim and Noxa in cerebral ischemia depended on RelA and the upstream kinase IKK (IkappaB kinase). RelA stimulated Bim and Noxa gene transcription in primary cortical neurons and bound to the promoter of both genes. Thus, the deleterious function in cerebral ischemia is specific for the NF-kappaB subunit RelA and may be mediated through Bim and Noxa.
Inta
Ioana
I
Department of Neurology, University of Heidelberg, 69120 Heidelberg, Germany.
Paxian
Stephan
S
Maegele
Ira
I
Zhang
Wen
W
Pizzi
Marina
M
Spano
PierFranco
P
Sarnico
Ilenia
I
Muhammad
Sajjad
S
Herrmann
Oliver
O
Inta
Dragos
D
Baumann
Bernd
B
Liou
Hsiou-Chi
HC
Schmid
Roland M
RM
Schwaninger
Markus
M
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000235:genetics; D051996:Transcription Factor RelA / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D016328:NF-kappa B; C408009:Pmaip1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051996:Transcription Factor RelA