Poly(ADP-ribosyl)ation is rapidly stimulated 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 Knock-In (PARP-1KI/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-1KI/KI mice develop normally, they were highly resistant to endotoxic shock, intestinal and renal ischemia-reperfusions, which were associated with reduced inflammation response in the target tissues and cells due to compromised production of specific inflammatory mediators. This study provides a novel insight to the function of PARP-1 in inflammation.
Noncleavable poly(ADP-ribose) polymerase-1 regulates the inflammation response in mice
DUGO, LAURA;CUZZOCREA, Salvatore;DI PAOLA, ROSANNA
2004-01-01
Abstract
Poly(ADP-ribosyl)ation is rapidly stimulated 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 Knock-In (PARP-1KI/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-1KI/KI mice develop normally, they were highly resistant to endotoxic shock, intestinal and renal ischemia-reperfusions, which were associated with reduced inflammation response in the target tissues and cells due to compromised production of specific inflammatory mediators. This study provides a novel insight to the function of PARP-1 in inflammation.Pubblicazioni consigliate
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