The functional role of poly(ADP-ribose)polymerase 1 as novel coactivator of NF-κB in inflammatory disorders

Abstract

Mammalian poly(ADP-ribose)polymerase 1 (PARP-1) is an abundant nuclear chromatin-associated protein and belongs to a large family of enzymes that catalyzes the transfer of ADP-ribose units from its substrate beta-nicotinamide adenine dinucleotide (NAD+) covalently to itself and other nuclear chromatin-associated proteins. PARP-1 knockout mice are protected against myocardial infarction, streptozotocin-induced diabetes, lipopolysaccharide-induced septic shock, and zymosan-induced multiple organ failure, indicating that PARP-1 is involved in the regulation of the pathogenesis of these disorders. PARP-1 and nuclear factor kappa B (NF-kappaB) have both been suggested to play a crucial role in inflammatory disorders. NF-kappaB encompasses a family of inducible transcription factors which play a crucial role in the regulation of genes involved in immune and inflammatory responses. Recent reports have shown that PARP-1 can act as a coactivator of NF-kappaB. These findings might provide new insights into the pathophysiology of different diseases such as type I diabetes and septic shock. The purpose of this review is to give a short overview of the current knowledge about PARP-1 and its functional and biochemical interactions with NF-kappaB. A more precise role for PARP-1 in NF-kappaB-dependent gene regulation and cellular metabolism during development of pathophysiological processes is discussed. Special considerations is given to the pathophysiological significance of these findings in terms of inflammatory disorders.

Identification of Poly (ADP-ribose) Polymerase-1 (PARP-1) as a Novel Krüppel-like Factor 8-interacting and -regulating Protein

“…Because the ZF DNA binding domain is required for KLF8 interaction with both importin-␤ and PARP-1, it is also possible that PARP-1 relays KLF8 from the importin and helps send KLF8 to promoter DNA of target genes in the nucleus. PARP-1 has been suggested to function as a bona fide transcriptional co-activator, as in the case of PARP-1 regulation of NF B-mediated transcription (26). In contrast, our results show that PARP-1 does not stay together with KLF8 at the promoter of cyclin D1, suggesting that PARP-1 likely works as a messenger to pass KLF8 from the nuclear importin to another co-activator, such as the histone acetyltransferases p300 and p300/CBP-associated factor transcription (11), at the promoter and lets the latter do the job of transcriptional co-activation.…”

Involvement of visfatin in palmitate-induced upregulation of inflammatory cytokines in hepatocytes

“…These enzymes are thought to be related to the inflammation process. Poly-ADP ribosyltransferase-1 was reported as a transcriptional coactivator of NF-κB, an important transcription factor in inflammation [22]. Recently, Van Gool et al [23] reported that intracellular NAD levels positively regulate TNF-α biosynthesis through sirtuin-6; the study was performed using monocytes and showed effects at the posttranscriptional level.…”

Microglial Activation in Stroke: Therapeutic Targets

“…22,213,214 PARP-1 interacts with NF-B, AP-1, and other proinflammatory transcription factors. [215][216][217] PARP-1 enzymatic activity is required for NF-B-mediated gene transcription and for many of the inflammatory responses in microglia. 22,214,218,219 Several PARP inhibitors are now commercially available.…”