Poly ADP-Ribosyl ation Activity and NF-KB-Dependent Gene Expression

Poly(ADP-Ribosyl)ation Activity and NF-KB-Dependent Gene Expression 

Model for the Function of the liansciiptional NF-KB/p300/EMtP-l Complex in Inflammatory Disorders 

Taken together, based on these data we propose a new pathophysiolc cal model for the dual function of PARP-1 in inflammatory disorders. In the ot nal models proposed by Szabo and colleagues, PARP-1 was thoi t to act only in parallel or downstream of NF-kB acdvation and induction of iNOS. However, results of different groups clearly suggest that PARP-1 acts as a coactivator of NF-kB upstream of the synthesis of iNOS, P-Selectin and other pro-inflammatory mediators durii the inflammation processes, independent of the enzymatic and DNA-binding activity of PARP-1.These results also explain why PARP-1(-/-) mice are extremely resistant against streptozotocin-induced diabetes and lethality induced by IPS. Moreover since NF-kB is involved in most diseases from which PARP-1 (-/-) mice are largely protected we propose that the PARP-l-coactivator function for NF-kB is a common mechanism and a critical molecular event involved in the pathc enesis of diflferent diseases such as septic shock, type-1 diabetes and arthritis. 

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