title: PED/PEA-15 inhibits hydrogen peroxide-induced apoptosis in Ins-1E pancreatic beta-cells via PLD-1.
abstract: The small scaffold protein PED/PEA-15 is involved in several different physiologic and pathologic processes, such as cell proliferation and survival, diabetes and cancer. PED/PEA-15 exerts an anti-apoptotic function due to its ability to interfere with both extrinsic and intrinsic apoptotic pathways in different cell types. Recent evidence shows that mice overexpressing PED/PEA-15 present larger pancreatic islets and increased beta-cells mass. In the present work we investigated PED/PEA-15 role in hydrogen peroxide-induced apoptosis in Ins-1E beta-cells. In pancreatic islets isolated from Tg(PED/PEA-15) mice hydrogen peroxide-induced DNA fragmentation was lower compared to WT islets. TUNEL analysis showed that PED/PEA-15 overexpression increases the viability of Ins-1E beta-cells and enhances their resistance to apoptosis induced by hydrogen peroxide exposure. The activity of caspase-3 and the cleavage of PARP-1 were markedly reduced in Ins-1E cells overexpressing PED/PEA-15 (Ins-1E(PED/PEA-15)). In parallel, we observed a decrease of the mRNA levels of pro-apoptotic genes Bcl-xS and Bad. In contrast, the expression of the anti-apoptotic gene Bcl-xL was enhanced. Accordingly, DNA fragmentation was higher in control cells compared to Ins-1E(PED/PEA-15) cells. Interestingly, the preincubation with propranolol, an inhibitor of the pathway of PLD-1, a known interactor of PED/PEA-15, responsible for its deleterious effects on glucose tolerance, abolishes the antiapoptotic effects of PED/PEA-15 overexpression in Ins-1E beta-cells. The same results have been obtained by inhibiting PED/PEA-15 interaction with PLD-1 in Ins-1E(PED/PEA-15). These results show that PED/PEA-15 overexpression is sufficient to block hydrogen peroxide-induced apoptosis in Ins-1E cells through a PLD-1 mediated mechanism.
authors.affiliation: Dipartimento di Scienze Mediche e Traslazionali dell'Università di Napoli "Federico II", Naples, Italy; URT dell'Istituto di Endocrinologia e Oncologia Sperimentale Gaetano Salvatore, Consiglio Nazionale delle Ricerche, Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fiory
authors.affiliation: Dipartimento di Scienze Mediche e Traslazionali dell'Università di Napoli "Federico II", Naples, Italy; URT dell'Istituto di Endocrinologia e Oncologia Sperimentale Gaetano Salvatore, Consiglio Nazionale delle Ricerche, Naples, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Parrillo
authors.affiliation: Dipartimento di Scienze Mediche e Traslazionali dell'Università di Napoli "Federico II", Naples, Italy; URT dell'Istituto di Endocrinologia e Oncologia Sperimentale Gaetano Salvatore, Consiglio Nazionale delle Ricerche, Naples, Italy.
authors.forename: Gregory Alexander
authors.initials: GA
authors.lastname: Raciti
authors.affiliation: Dipartimento di Scienze Mediche e Traslazionali dell'Università di Napoli "Federico II", Naples, Italy; URT dell'Istituto di Endocrinologia e Oncologia Sperimentale Gaetano Salvatore, Consiglio Nazionale delle Ricerche, Naples, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Zatterale
authors.affiliation: Dipartimento di Scienze Mediche e Traslazionali dell'Università di Napoli "Federico II", Naples, Italy; URT dell'Istituto di Endocrinologia e Oncologia Sperimentale Gaetano Salvatore, Consiglio Nazionale delle Ricerche, Naples, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nigro
authors.affiliation: Dipartimento di Scienze Mediche e Traslazionali dell'Università di Napoli "Federico II", Naples, Italy; URT dell'Istituto di Endocrinologia e Oncologia Sperimentale Gaetano Salvatore, Consiglio Nazionale delle Ricerche, Naples, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Mirra
authors.affiliation: Dipartimento di Scienze Mediche e Traslazionali dell'Università di Napoli "Federico II", Naples, Italy; URT dell'Istituto di Endocrinologia e Oncologia Sperimentale Gaetano Salvatore, Consiglio Nazionale delle Ricerche, Naples, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Falco
authors.affiliation: Dipartimento di Scienze Mediche e Traslazionali dell'Università di Napoli "Federico II", Naples, Italy; URT dell'Istituto di Endocrinologia e Oncologia Sperimentale Gaetano Salvatore, Consiglio Nazionale delle Ricerche, Naples, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Ulianich
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche e Ambientali, Università del Salento, Lecce, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Di Jeso
authors.affiliation: Dipartimento di Scienze Mediche e Traslazionali dell'Università di Napoli "Federico II", Naples, Italy; URT dell'Istituto di Endocrinologia e Oncologia Sperimentale Gaetano Salvatore, Consiglio Nazionale delle Ricerche, Naples, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Formisano
authors.affiliation: Dipartimento di Scienze Mediche e Traslazionali dell'Università di Napoli "Federico II", Naples, Italy; URT dell'Istituto di Endocrinologia e Oncologia Sperimentale Gaetano Salvatore, Consiglio Nazionale delle Ricerche, Naples, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Miele
authors.affiliation: Dipartimento di Scienze Mediche e Traslazionali dell'Università di Napoli "Federico II", Naples, Italy; URT dell'Istituto di Endocrinologia e Oncologia Sperimentale Gaetano Salvatore, Consiglio Nazionale delle Ricerche, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Beguinot
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D010739:Phospholipase D / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D051381:Rats
chemical_list: D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; D006861:Hydrogen Peroxide; D010739:Phospholipase D; C106801:phospholipase D1