A splice variant of stress response gene ATF3 counteracts NF-kappaB-dependent anti-apoptosis through inhibiting recruitment of CREB-binding protein/p300 coactivator.
Activating transcription factor (ATF) 3 plays a role in determining cell fate and generates a variety of alternatively spliced isoforms in stress response. We have reported previously that splice variant ATF3deltaZip2, which lacks the leucine zipper region, is induced in response to various stress stimuli. However, its biological function has not been elucidated. By using cells treated with tumor necrosis factor-alpha and actinomycin D or cells overexpressing ATF3deltaZip2, we showed that ATF3deltaZip2 sensitizes cells to apoptotic cell death in response to tumor necrosis factor-alpha, at least in part through suppressing nuclear factor (NF)-kappaB-dependent transcription of anti-apoptotic genes such as cIAP2 and XIAP. ATF3deltaZip2 interacts with a p65 (RelA)-cofactor complex containing CBP/p300 and HDAC1 at NF-kappaB sites of the proximal promoter region of the cIAP2 gene in vivo and down-regulates the recruitment of CBP/p300. Our study revealed that ATF3deltaZip2 counteracts anti-apoptotic activity of NF-kappaB, at least in part, by displacing positive cofactor CBP/p300 and provides insight into the mechanism by which ATF3 regulates cell fate through alternative splicing in stress response.
Hua
Bayin
B
Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
Tamamori-Adachi
Mimi
M
Luo
Yang
Y
Tamura
Kiyoshi
K
Morioka
Masaki
M
Fukuda
Mizue
M
Tanaka
Yujiro
Y
Kitajima
Shigetaka
S
D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000256:Adenoviridae / Q000235:genetics; D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D003609:Dactinomycin / Q000494:pharmacology; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D014644:Genetic Variation; D005822:Genetic Vectors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D051700:Activating Transcription Factor 3; C497108:Atf3 protein, rat; D016328:NF-kappa B; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003609:Dactinomycin; D006655:Histone Deacetylases