title: Poly(ADP-ribose) polymerase-1 and its cleavage products differentially modulate cellular protection through NF-kappaB-dependent signaling.
abstract: Poly(ADP-ribose) polymerase-1 (PARP-1) and its cleavage products regulate cell viability and NF-kappaB activity when expressed in neurons. PARP-1 cleavage generates a 24 kDa (PARP-1(24)) and an 89 kDa fragment (PARP-1(89)). Compared to WT (PARP-1WT), the expression of an uncleavable PARP-1 (PARP-1(UNCL)) or of PARP-1(24) conferred protection from oxygen/glucose deprivation (OGD) or OGD/restoration of oxygen and glucose (ROG) damage in vitro, whereas expression of PARP-1(89) was cytotoxic. Viability experiments were performed in SH-SY5Y, a human neuroblastoma cell line, as well as in rat primary cortical neurons. Following OGD, the higher viability in the presence of PARP-1UNCL or PARP-1(24) was not accompanied with decreased formation of poly(ADP-riboses) or higher NAD levels. PARP-1 is a known cofactor for NF-kappaB, hence we investigated whether PARP-1 cleavage influences the inflammatory response. All PARP-1 constructs mimicked PARP-1WT in regard to induction of NF-kappaB translocation into the nucleus and its increased activation during ischemic challenge. However, expression of PARP-1(89) construct induced significantly higher NF-kB activity than PARP-1WT; and the same was true for NF-kappaB-dependent iNOS promoter binding activity. At a protein level, PARP-1UNCL and PARP-1(24) decreased iNOS (and lower levels of iNOS transcript) and COX-2, and increased Bcl-xL The increased levels of NF-kB and iNOS transcriptional activities, seen with cytotoxic PARP-189, were accompanied by higher protein expression of COX-2 and iNOS (and higher levels of INOS transcript) and lower protein expression of Bcl-xL Taken together, these findings suggest that PARP-1 cleavage products may regulate cellular viability and inflammatory responses in opposing ways during in vitro models of "ischemia".
authors: Paola
authors: P
authors: Castri
authors: Yang-Ja
authors: YJ
authors: Lee
authors: Todd
authors: T
authors: Ponzio
authors: Dragan
authors: D
authors: Maric
authors: Maria
authors: M
authors: Spatz
authors: Joliet
authors: J
authors: Bembry
authors: John
authors: J
authors: Hallenbeck
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C499320:PARP1 protein, human; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases