PARP Goes Transcription

Kraus, W. Lee; Lis, John T.

doi:10.1016/s0092-8674(03)00433-1

Cited by 489 publications

(464 citation statements)

References 33 publications

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“…We chose to study the effect of Atiprimod on the activation of caspase 3, the downstream 'executioner' caspase (Nicholson, 1999) manner, with the maximum effect achieved after 4 h. Furthermore, incubation of U266-B1 cells for 1 h with Atiprimod induced a dosedependent increase in caspase 3 cleavage ( Figure 6C, lower panel). Activated caspase 3 abrogates the effect of substrates that protect cellular integrity, such as the DNA-repair enzyme PARP (Nicholson, 1999;Kraus and Lis, 2003). When we exposed the cells to Atiprimod, we found a dose-dependent increase in cleaved PARP protein levels, with the maximum effect achieved at a concentration of 8 mM ( Figure 6C, lower panel).…”

Section: Atiprimod Induces Apoptosis By Activating the Caspase Pathwaymentioning

confidence: 90%

Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells

et al. 2005

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Multiple myeloma (MM) accounts for 1 % of all cancer deaths. Although treated aggressively, almost all myelomas eventually recur and become resistant to treatment. Atiprimod 5] decane dimaleate) has exerted anti-inflammatory activities and inhibited oeteoclast-induced bone resorption in animal models and been well tolerated in patients with rheumatoid arthritis in phase I clinical trials. Therefore, we investigated its activity in MM cells and its mechanism of action. We found that Atiprimod inhibited proliferation of the myeloma cell lines U266-B1, OCI-MY5, MM-1, and MM-1R in a timeand dose-dependent manner. Atiprimod blocked U266-B1 myeloma cells in the G 0 /G 1 phase, preventing cell cycle progression. Furthermore, Atiprimod inhibited signal transducer and activator of transcription (STAT) 3 activation, blocking the signalling pathway of interleukin-6, which contributes to myeloma cell proliferation and survival, and downregulated the antiapoptotic proteins Bcl-2, Bcl-X L , and Mcl-1. Incubation of U266-B1 myeloma cells with Atiprimod induced apoptosis through the activation of caspase 3 and subsequent cleavage of the DNA repair enzyme poly(adenosine diphosphate-ribose) polymerase. Finally, Atiprimod suppressed myeloma colony-forming cell proliferation in fresh marrow cells from five patients with newly diagnosed MM in a dose-dependent fashion. These data suggest that Atiprimod has a role in future therapies for MM.

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Section: Atiprimod Induces Apoptosis By Activating the Caspase Pathwaymentioning

confidence: 90%

Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells

et al. 2005

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“…Although originally characterized as a key factor in DNA repair pathways, a wealth of studies over the past decade have demonstrated a role for PARP-1 in the regulation of gene expression under basal, signal-activated, and stress-activated conditions [1][2][3]. Recent studies using a variety of experimental approaches have highlighted the role of PARP-1 in at least four distinct modes of transcriptional regulation (see below) and provided new insights about the cellular signaling systems that interface with PARP-1 in the nucleus.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional control by PARP-1: chromatin modulation, enhancer-binding, coregulation, and insulation

Kraus

2008

Current Opinion in Cell Biology

373

336

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SummaryThe regulation of gene expression requires a wide array of protein factors that can modulate chromatin structure, act at enhancers, function as transcriptional coregulators, or regulate insulator function. Poly(ADP-ribose) polymerase-1 (PARP-1), an abundant and ubiquitous nuclear enzyme that catalyzes the NAD + -dependent addition of ADP-ribose polymers on a variety of nuclear proteins, has been implicated in all of these functions. Recent biochemical, genomic, proteomic, and cell-based studies have highlighted the role of PARP-1 in each of these processes and provided new insights about the molecular mechanisms governing PARP-1-dependent regulation of gene expression. In addition, these studies have demonstrated how PARP-1 functions as an integral part of cellular signaling pathways that culminate in gene regulatory outcomes.

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“…A similar distribution pattern was observed for NF-κB p65 subunit, which is known to serve as a repressor of claudin-5 and to be PARP-dependent for its activity 32,33 ( Figure 6E). The above findings have led us to conclude that PARP is involved in opening transcriptional complexes 34 and induction of TJ protein transcription.…”

Section: Parp Inhibitors Diminish Expression Of Proinflammatory Mediamentioning

confidence: 89%

“…Anti-inflammatory effects of PARP have been documented in several in vivo and in vitro studies; 33,34,36 however, data on PARP inhibition in endothelial cells are just emerging. We selectively inhibited PARP in brain endothelium and showed that monocyte adhesion to TNFα-stimulated BMVEC and migration across BMVEC monolayers were attenuated by PARP inhibition (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

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Poly(ADP-ribose) Polymerase-1 Inhibition in Brain Endothelium Protects the Blood—Brain Barrier under Physiologic and Neuroinflammatory Conditions

Rom

Zuluaga-Ramirez

Dykstra

et al. 2014

J Cereb Blood Flow Metab

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Blood-brain barrier (BBB) dysfunction seen in neuroinflammation contributes to mortality and morbidity in multiple sclerosis, encephalitis, traumatic brain injury, and stroke. Identification of molecular targets maintaining barrier function is of clinical relevance. We used a novel in vivo model of localized aseptic meningitis where tumor necrosis factor alpha (TNFα) was introduced intracerebrally and surveyed cerebral vascular changes and leukocyte-endothelium interactions by intravital videomicroscopy. Poly (ADP-ribose) polymerase-1 (PARP) inhibition significantly reduced leukocyte adhesion to and migration across brain endothelium in cortical microvessels. PARP inactivation diminished BBB permeability in an in vivo model of systemic inflammation. PARP suppression in primary human brain microvascular endothelial cells (BMVEC), an in vitro model of BBB, enhanced barrier integrity and augmented expression of tight junction proteins. PARP inhibition in BMVEC diminished human monocyte adhesion to TNFα-activated BMVEC (up to 65%) and migration (80-100%) across BBB models. PARP suppression decreased expression of adhesion molecules and decreased activity of GTPases (controlling BBB integrity and monocyte migration across the BBB). PARP inhibitors down-regulated expression of inflammatory genes and dampened secretion of pro-inflammatory factors increased by TNFα in BMVEC. These results point to PARP suppression as a novel approach to BBB protection in the setting of endothelial dysfunction caused by inflammation. PARP-1 is a member of a family of NAD-dependent enzymes that is responsible for~80% of cellular poly(ADP-ribose) formation. 1 Poly(ADP-ribosyl)ation is a post-translational modification of proteins with widespread effects on diverse cellular functions including gene expression, differentiation and cell death. 2 As a scaffold protein and as an enzyme, PARP-1 (further referred to in the text as PARP) is a key component of the transcriptional machinery that controls chromatin architecture, histone shuttling, and spatial organization of transcription-regulating supramolecular complexes, 2 thereby regulating inflammationassociated genes.In this article, for the first time, we show mechanisms of the modulatory effects of PARP inhibition in brain endothelium. Previous studies have demonstrated anti-inflammatory effects of PARP suppression in animal models of traumatic brain injury, multiple sclerosis (MS), meningitis, and stroke, [3][4][5] where PARP inhibitors reduced edema, leukocyte infiltration and neuroinflammation, and decreased intercellular adhesion molecule 1 (ICAM-1) expression. 4,6 PARP inhibitors have now reached the stage of

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PARP Goes Transcription

Cited by 489 publications

References 33 publications

Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells

Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells

Transcriptional control by PARP-1: chromatin modulation, enhancer-binding, coregulation, and insulation

Poly(ADP-ribose) Polymerase-1 Inhibition in Brain Endothelium Protects the Blood—Brain Barrier under Physiologic and Neuroinflammatory Conditions

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