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|Título:||Noncleavable poly(ADP-ribose) polymerase-1 regulates the inflammatbn response in mice|
Di Paola, R
|Palavras-chave:||Medicine, Research & Experimental|
|Editora:||AMER SOC CLINICAL INVESTIGATION INC|
|Citação:||JOURNAL OF CLINICAL INVESTIGATION. - Vol. 114, n. 8 (OCT 2004), p. 1072-1081|
|Resumo:||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, DEVD214, 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.|
|Aparece nas colecções:||FF - Produção Científica 2000-2009|
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