A splice variant of stress response gene ATF3 counteracts NF-κB-dependent anti-apoptosis through inhibiting recruitment of CREB-binding protein/p300 coactivator

Abstract 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 ATF3ΔZip2, 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-α and actinomycin D or cells overexpressing ATF3ΔZip2, we showed that ATF3ΔZip2 sensitizes cells to apoptotic cell death in response to tumor necrosis factor-α, at least in part through suppressing nuclear factor (NF)-κB-dependent transcription of anti-apoptotic genes such as cIAP2 and XIAP. ATF3ΔZip2 interacts with a p65 (RelA)-cofactor complex containing CBP/p300 and HDAC1 at NF-κB sites of the proximal promoter region of the cIAP2 gene in vivo and down-regulates the recruitment of CBP/p300. Our study revealed that ATF3ΔZip2 counteracts anti-apoptotic activity of NF-κB, 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.