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Poly(ADP-ribose) polymerase 1 is a key regulator of estrogen receptor ?-dependent gene transcription.

ABSTRACT: Activation of nuclear receptor estrogen receptor ? (ER?) exerts cardiovascular protective effects by modulating the expression of ER? target genes. However, the underlying mechanism remains unclear. PARP1 is a ubiquitous multifunctional nuclear enzyme. In this study, we examined the interplay between PARP1 and ER?, and identified PARP1 as an important regulator of ER?-dependent transcription. We showed that PARP1 could directly bind to ER?, and ER? could be poly(ADP-ribosyl)ated by PARP1. Poly(ADP-ribosyl)ation increased ER? binding to estrogen response element (ERE) present in the promoter of target genes and promoted ER?-mediated gene transcription. Estradiol, the ligand of ER?, increased PARP enzymatic activity and enhanced poly(ADP-ribosyl)ation of ER?. Upon treatment with estradiol, ER? binding to ERE- and ER?-dependent gene expression was dramatically increased in cultured vascular smooth muscle cells (VSMCs). Inhibition of PARP1 by PARP inhibitor or PARP1 siRNA decreased ER? binding to ERE and prevented ER?-dependent gene transcription in VSMCs. Further studies revealed that PARP1 served as an indispensible component for the formation of the ER?-ERE complex by directly interacting with ER?. Thus, our results identify PARP1 as a key regulator of ER? in controlling ER? transactivation.

SUBMITTER: Zhang F

PROVIDER: S-EPMC3630903 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Poly(ADP-ribose) polymerase 1 is a key regulator of estrogen receptor α-dependent gene transcription.

Zhang Fengxiao F Wang Yan Y Wang Lin L Luo Xi X Huang Kun K Wang Cheng C Du Meng M Liu Fangmei F Luo Ting T Huang Dan D Huang Kai K

The Journal of biological chemistry 20130314 16

Activation of nuclear receptor estrogen receptor α (ERα) exerts cardiovascular protective effects by modulating the expression of ERα target genes. However, the underlying mechanism remains unclear. PARP1 is a ubiquitous multifunctional nuclear enzyme. In this study, we examined the interplay between PARP1 and ERα, and identified PARP1 as an important regulator of ERα-dependent transcription. We showed that PARP1 could directly bind to ERα, and ERα could be poly(ADP-ribosyl)ated by PARP1. Poly(A ...[more]

PMID: 23493398

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Project description:Poly(ADP-ribose) polymerase 3 (PARP3) is a member of the PARP family of enzymes. It is structurally related to the well characterized type member PARP1 that orchestrates DNA strand break repair and cell death by the synthesis of poly(ADP-ribose). In contrast, the functions of PARP3 are undefined. We have used several in vitro and in vivo approaches to examine the possible functions of PARP3 as a transcriptional regulator, a function suggested from its previously reported association with several Polycomb group (PcG) proteins. A ChIP-chip analysis of PARP3 gene occupancy in the human neuroblastoma cell line SK-N-SH reveals that PARP3 is preferentially associated with developmental genes and is significantly enriched around the transcriptional start site of several genes encoding neuronal and sensory placodes specifiers, such as SOX9, DLX3 and DLX4. Using zebrafish as a vertebrate animal model, we demonstrate that Parp3 plays a key role in ectodermal and neural crest specification. Morpholino oligonucleotide-directed inhibition of parp3 expression in zebrafish impairs the expression of the neural crest cell specifier sox9a and of dlx3b/dlx4b, the formation of cranial sensory placodes, inner ears and pectoral fins. It delays pigmentation and severely impedes the development of the median fin fold and tail bud. Our findings demonstrate that Parp3 is crucial in the early stages of zebrafish development, possibly by exerting its transcriptional regulatory functions as early as during the specification of the neural plate border. ChIP were conducted as described (Rodrigue et al. 2006). PARP3 was immunoprecipitated from 3 x 10^7 SK-N-SH cells with a commercial anti-PARP3 (Enzo Life Sciences ALX-210-541). In control ChIP, PARP3 antibodies were replaced by rabbit IgG. Two independent PARP3 and control ChIP-chip experiments were achieved. The DNA was amplified using LM-PCR and labelled with Cy5 (PARP3) and Cy3 (IgG) before hybridization on Agilent Human promoter arrays (two 244k chip per ChIP for a total of 4 chips). Detailed protocols can be found at http://www.ircm.qc.ca/microsites/francoisrobert/en. Regions significantly enriched for PARP3 relative to IgG were identified as described (Lee et al. 2006).

Project description:UNLABELLED:Poly (ADP-ribose) polymerase 1 (PARP-1) is a constitutive enzyme, the major isoform of the PARP family, which is involved in the regulation of DNA repair, cell death, metabolism, and inflammatory responses. Pharmacological inhibitors of PARP provide significant therapeutic benefits in various preclinical disease models associated with tissue injury and inflammation. However, our understanding the role of PARP activation in the pathophysiology of liver inflammation and fibrosis is limited. In this study we investigated the role of PARP-1 in liver inflammation and fibrosis using acute and chronic models of carbon tetrachloride (CCl4 )-induced liver injury and fibrosis, a model of bile duct ligation (BDL)-induced hepatic fibrosis in vivo, and isolated liver-derived cells ex vivo. Pharmacological inhibition of PARP with structurally distinct inhibitors or genetic deletion of PARP-1 markedly attenuated CCl4 -induced hepatocyte death, inflammation, and fibrosis. Interestingly, the chronic CCl4 -induced liver injury was also characterized by mitochondrial dysfunction and dysregulation of numerous genes involved in metabolism. Most of these pathological changes were attenuated by PARP inhibitors. PARP inhibition not only prevented CCl4 -induced chronic liver inflammation and fibrosis, but was also able to reverse these pathological processes. PARP inhibitors also attenuated the development of BDL-induced hepatic fibrosis in mice. In liver biopsies of subjects with alcoholic or hepatitis B-induced cirrhosis, increased nitrative stress and PARP activation was noted. CONCLUSION:The reactive oxygen/nitrogen species-PARP pathway plays a pathogenetic role in the development of liver inflammation, metabolism, and fibrosis. PARP inhibitors are currently in clinical trials for oncological indications, and the current results indicate that liver inflammation and liver fibrosis may be additional clinical indications where PARP inhibition may be of translational potential.

Dataset Information

Poly(ADP-ribose) polymerase 1 is a key regulator of estrogen receptor ?-dependent gene transcription.

Publications

Poly(ADP-ribose) polymerase 1 is a key regulator of estrogen receptor α-dependent gene transcription.

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