| First Author | Pétrilli V | Year | 2004 |
| Journal | J Clin Invest | Volume | 114 |
| Issue | 8 | Pages | 1072-81 |
| PubMed ID | 15489954 | Mgi Jnum | J:93479 |
| Mgi Id | MGI:3057101 | Doi | 10.1172/JCI21854 |
| Citation | Petrilli V, et al. (2004) Noncleavable poly(ADP-ribose) polymerase-1 regulates the inflammation response in mice. J Clin Invest 114(8):1072-81 |
| abstractText | Poly(ADP-ribosyl)ation is rapidly formed in cells following DNA damage and is regulated by poly(ADP-ribose) polymerase-1 (PARP-1). PARP-1 is known to be involved in various cellular processes, such as DNA repair, genomic stability, transcription, and cell death. During apoptosis, PARP-1 is cleaved by caspases to generate 89-kDa and 24-kDa fragments, a hallmark of apoptosis. This cleavage is thought to be a regulatory event for cellular death. In order to understand the biological significance of PARP-1 cleavage, we generated a PARP-1 knockin (PARP-1(KI/KI)) mouse model, in which the caspase cleavage site of PARP-1, DEVD(214), was mutated to render the protein resistant to caspases during apoptosis. While PARP-1(KI/KI) mice developed normally, they were highly resistant to endotoxic shock and to intestinal and renal ischemia-reperfusions, which were associated with reduced inflammatory responses in the target tissues and cells due to the compromised production of specific inflammatory mediators. Despite normal binding of NF-kappaB to DNA, NF-kappaB-mediated transcription activity was impaired in the presence of caspase-resistant PARP-1. This study provides a novel insight into the function of PARP-1 in inflammation and ischemia-related pathophysiologies. |
