Poly(ADP-ribose) polymerase-1 and its cleavage products differentially modulate cellular protection through NF-kB-dependent signaling

被引:48
作者
Castri, Paola [1 ]
Lee, Yang-ja [1 ]
Ponzio, Todd [2 ]
Maric, Dragan [3 ]
Spatz, Maria [1 ]
Bembry, Joliet [1 ]
Hallenbeck, John [1 ]
机构
[1] NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA
[2] NINDS, Lab Neurochem, NIH, Bethesda, MD 20892 USA
[3] NINDS, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA
来源
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH | 2014年 / 1843卷 / 03期
关键词
PARP-1; ARTD1; Brain ischemia; OGD; NF-kB; ADP-RIBOSE POLYMERASE-1; KAPPA-B ACTIVATION; CEREBRAL-ISCHEMIA; DNA-BINDING; INFLAMMATION; APOPTOSIS; TRANSCRIPTION; DISEASE; PARP-1; CELLS;
D O I
10.1016/j.bbamcr.2013.12.005
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Poly(ADP-ribose) polymerase-1 (PARP-1) and its cleavage products regulate cell viability and NF-kB 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-1(WT)), 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-189 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-1(UNCL) 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-kB, hence we investigated whether PARP-1 cleavage influences the inflammatory response. All PARP-1 constructs mimicked PARP-1(WT) in regard to induction of NF-kB translocation into the nucleus and its increased activation during ischemic challenge. However, expression of PARP-189 construct induced significantly higher NF-kB activity than PARP-1; and the same was true for NF-kB-dependent iNOS promoter binding activity. At a protein level, PARP-1(UNCL) and PARP-1(24) decreased iNOS (and lower levels of iNOS transcript) and COX-2, and increased Bc1-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 Bc1-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". Published by Elsevier B.V.
引用
收藏
页码:640 / 651
页数:12
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