CEBPA exerts a specific and biologically important proapoptotic role in pancreatic β cells through its downstream network targets

Transcription factor CEBPA has been widely studied for its involvement in hematopoietic cell differentiation and causal role in hematological malignancies. We demonstrate here that it also performs a causal role in cytokine-induced apoptosis of pancreas beta cells. Treatment of two mouse pancreatic alpha and beta cell lines (alpha TC1-6 and beta TC1) with proinflammatory cytokines IL-1 beta, IFN-gamma, and TNF-alpha at doses that specifically induce apoptosis of beta TC1 significantly increased the amount of mRNA and protein encoded by Cebpa and its proapoptotic targets, Arl6ip5 and Tnfrsf10b, in beta TC1 but not in alpha TC1-6. Cebpa knockdown in beta TC1 significantly decreased cytokine-induced apoptosis, together with the amount of Arl6ip5 and Tnfrsf10b. Analysis of the network comprising CEBPA, its targets, their first interactants, and proteins encoded by genes known to regulate cytokine-induced apoptosis in pancreatic beta cells (genes from the apoptotic machinery and from MAPK and NF kappa B pathways) revealed that CEBPA, ARL6IP5, TNFRSF10B, TRAF2, and UBC are the top five central nodes. In silico analysis further suggests TRAF2 as trait d'union node between CEBPA and the NF kappa B pathway. Our results strongly suggest that Cebpa is a key regulator within the apoptotic network activated in pancreatic beta cells during insulitis, and Arl6ip5, Tnfrsf10b, Traf2, and Ubc are key executioners of this program.