title: CEBPA exerts a specific and biologically important proapoptotic role in pancreatic β cells through its downstream network targets.
abstract: 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 β cells. Treatment of two mouse pancreatic α and β cell lines (αTC1-6 and βTC1) with proinflammatory cytokines IL-1β, IFN-γ, and TNF-α at doses that specifically induce apoptosis of βTC1 significantly increased the amount of mRNA and protein encoded by Cebpa and its proapoptotic targets, Arl6ip5 and Tnfrsf10b, in βTC1 but not in αTC1-6. Cebpa knockdown in βTC1 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 β cells (genes from the apoptotic machinery and from MAPK and NFkB 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 NFkB pathway. Our results strongly suggest that Cebpa is a key regulator within the apoptotic network activated in pancreatic β cells during insulitis, and Arl6ip5, Tnfrsf10b, Traf2, and Ubc are key executioners of this program.
authors.affiliation: Unit of Molecular, Genome and Complex Systems BioMedicine, Department "Gian Filippo Ingrassia," University of Catania, Catania 95123, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Barbagallo
authors.affiliation: Unit of Molecular, Genome and Complex Systems BioMedicine, Department "Gian Filippo Ingrassia," University of Catania, Catania 95123, Italy.
authors.forename: Angelo Giuseppe
authors.initials: AG
authors.lastname: Condorelli
authors.affiliation: Department of Molecular and Clinic BioMedicine, University of Catania, Catania 95122, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Piro
authors.affiliation: Department of Molecular and Clinic BioMedicine, University of Catania, Catania 95122, Italy.
authors.forename: Nunziatina
authors.initials: N
authors.lastname: Parrinello
authors.affiliation: Copenhagen Diabetes Research Center (DIRECT), Herlev University Hospital, 2730 Herlev, Denmark.
authors.forename: Tina
authors.initials: T
authors.lastname: Fløyel
authors.affiliation: Unit of Molecular, Genome and Complex Systems BioMedicine, Department "Gian Filippo Ingrassia," University of Catania, Catania 95123, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Ragusa
authors.affiliation: Department of Molecular and Clinic BioMedicine, University of Catania, Catania 95122, Italy.
authors.forename: Agata Maria
authors.initials: AM
authors.lastname: Rabuazzo
authors.affiliation: Copenhagen Diabetes Research Center (DIRECT), Herlev University Hospital, 2730 Herlev, Denmark.
authors.forename: Joachim
authors.initials: J
authors.lastname: Størling
authors.affiliation: Department of Molecular and Clinic BioMedicine, University of Catania, Catania 95122, Italy purrello@unict.it dipietro@unict.it fpurrell@unict.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Purrello
authors.affiliation: Unit of Molecular, Genome and Complex Systems BioMedicine, Department "Gian Filippo Ingrassia," University of Catania, Catania 95123, Italy purrello@unict.it dipietro@unict.it fpurrell@unict.it.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Di Pietro
authors.affiliation: Unit of Molecular, Genome and Complex Systems BioMedicine, Department "Gian Filippo Ingrassia," University of Catania, Catania 95123, Italy purrello@unict.it dipietro@unict.it fpurrell@unict.it.
authors.forename: Michele
authors.initials: M
authors.lastname: Purrello
mesh_terms: D000818:Animals; D017209:Apoptosis; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D053583:Interleukin-1beta; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases