Abstract A59: Life and death decision by E2F1 depends on Jab1-mediated expression of E2F apoptotic target genes and is counteracted by PI3K activation.

Rb regulation of cell cycle progression and tumorigenesis is dependent on its control of E2F transcription factor function, a family of proteins that initiate both cell proliferation and cell death. Several classes of E2F target genes have been categorized based on their roles in DNA replication, G2/M & mitosis, apoptosis, DNA repair, etc. However, the mechanisms controlling appropriate expression of genes responsible for these cell fates is poorly understood. We previously showed that Jab1 promotes E2F1-induced apoptosis but not DNA replication as an E2F1-specific binding partner. In this study, we performed gene expression analysis to better understand the control of E2F1 function by Jab1/CSN5. Microarray assay revealed a significant number of apoptotic E2F target genes such as Cyp26b1 and AMPKα2 are profoundly impaired by Jab1 shRNA knockdown, whereas DNA replication genes are generally still highly expressed. The findings of microarray were further confirmed using quantitative real-time PCR. Subsequent chromatin immunoprecipitation indicates that Jab1/E2F1 complex resides on the promoters of E2F1 apoptotic and G2/M, but not DNA replication targets genes. Meanwhile, we found that PI3K activation blocks expression of E2F1/Jab1 co-induced apoptotic target genes and apoptosis induction at least in part by interfering with formation of the pro-apoptotic Jab1/E2F1 complex as determined by co-immunoprecipitation. More importantly, we detected a highly significant correlation between elevated Jab1 levels and PI3K activity in breast, ovarian, lung and prostate cancers. These findings suggest the possibility that Jab1, when elevated in these tumors, may evade triggering tumor-suppressive E2F1 apoptosis and instead induce proliferation through the frequent, simultaneous co-activation of PI3K activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A59.