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Article ; Online: Nuclear ADP-ribosylation drives IFNγ-dependent STAT1α enhancer formation in macrophages.

Gupte, Rebecca / Nandu, Tulip / Kraus, W Lee

2021 Volume 12, Issue 1, Page(s) 3931

Abstract: STAT1α is a key transcription factor driving pro-inflammatory responses in macrophages. We found that the interferon gamma (IFNγ)-regulated transcriptional program in macrophages is controlled by ADP-ribosylation (ADPRylation) of STAT1α, a post- ... ...

Abstract	STAT1α is a key transcription factor driving pro-inflammatory responses in macrophages. We found that the interferon gamma (IFNγ)-regulated transcriptional program in macrophages is controlled by ADP-ribosylation (ADPRylation) of STAT1α, a post-translational modification resulting in the site-specific covalent attachment of ADP-ribose moieties. PARP-1, the major nuclear poly(ADP-ribose) polymerase (PARP), supports IFNγ-stimulated enhancer formation by regulating the genome-wide binding and IFNγ-dependent transcriptional activation of STAT1α. It does so by ADPRylating STAT1α on specific residues in its DNA-binding domain (DBD) and transcription activation (TA) domain. ADPRylation of the DBD controls STAT1α binding to its cognate DNA elements, whereas ADPRylation of the TA domain regulates enhancer activation by modulating STAT1α phosphorylation and p300 acetyltransferase activity. Loss of ADPRylation at either site leads to diminished IFNγ-dependent transcription and downstream pro-inflammatory responses. We conclude that PARP-1-mediated ADPRylation of STAT1α drives distinct enhancer activation mechanisms and is a critical regulator of inflammatory responses in macrophages.
MeSH term(s)	ADP-Ribosylation ; Animals ; Binding Sites ; DNA/metabolism ; Enhancer Elements, Genetic ; Female ; Gene Knockdown Techniques ; HEK293 Cells ; Humans ; Inflammation/metabolism ; Inflammation/pathology ; Interferon-gamma/metabolism ; Macrophages/pathology ; Macrophages/physiology ; Male ; Mice, Inbred C57BL ; Phosphorylation ; Poly (ADP-Ribose) Polymerase-1/genetics ; Poly (ADP-Ribose) Polymerase-1/metabolism ; STAT1 Transcription Factor/chemistry ; STAT1 Transcription Factor/genetics ; STAT1 Transcription Factor/metabolism ; Transcriptional Activation ; Mice
Chemical Substances	STAT1 Transcription Factor ; Stat1 protein, mouse ; Interferon-gamma (82115-62-6) ; DNA (9007-49-2) ; Parp1 protein, mouse (EC 2.4.2.30) ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30)
Language	English
Publishing date	2021-06-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-24225-2
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Article ; Online: Combinatorial Treatment with PARP-1 Inhibitors and Cisplatin Attenuates Cervical Cancer Growth through Fos-Driven Changes in Gene Expression.

Gupte, Rebecca / Lin, Ken Y / Nandu, Tulip / Lea, Jayanthi S / Kraus, W Lee

Molecular cancer research : MCR

2022 Volume 20, Issue 8, Page(s) 1183–1192

Abstract: Cervical cancer continues to be a significant cause of cancer-related deaths in women. The most common treatment for cervical cancer involves the use of the drug cisplatin in conjunction with other therapeutics. However, the development of cisplatin ... ...

Abstract	Cervical cancer continues to be a significant cause of cancer-related deaths in women. The most common treatment for cervical cancer involves the use of the drug cisplatin in conjunction with other therapeutics. However, the development of cisplatin resistance in patients can hinder the efficacy of these treatments, so alternatives are needed. In this study, we found that PARP inhibitors (PARPi) could attenuate the growth of cells representing cervical adenocarcinoma and cervical squamous cell carcinoma. Moreover, a combination of PARPi with cisplatin increased cisplatin-mediated cytotoxicity in cervical cancer cells. This was accompanied by a dramatic alteration of the transcriptome. The FOS gene, which encodes the transcription factor Fos, was one of the most highly upregulated genes in the dual treatment condition, leading to increased Fos protein levels, greater Fos binding to chromatin, and the subsequent induction of Fos target genes. Increased expression of Fos was sufficient to hinder cervical cancer growth, as shown by ectopic expression of Fos in cervical cancer cells. Conversely, Fos knockdown enhanced cell growth. Collectively, these results indicate that by inducing FOS expression, PARPi treatment in combination with cisplatin leads to inhibition of cervical cancer proliferation, likely through a Fos-specific gene expression program. Implications: Our observations, which link the gene regulatory effects of PARPi + cisplatin to the growth inhibitory effects of FOS expression in cervical cancer cells, strengthen the rationale for using PARPi with cisplatin as a therapy for cervical cancer.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Apoptosis ; Cisplatin/pharmacology ; Drug Resistance, Neoplasm ; Female ; Gene Expression ; Humans ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-fos/genetics ; Transcription Factors/genetics ; Uterine Cervical Neoplasms/drug therapy ; Uterine Cervical Neoplasms/genetics ; Uterine Cervical Neoplasms/pathology
Chemical Substances	Antineoplastic Agents ; FOS protein, human ; Poly(ADP-ribose) Polymerase Inhibitors ; Proto-Oncogene Proteins c-fos ; Transcription Factors ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2022-05-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2098788-2
ISSN	1557-3125 ; 1541-7786
ISSN (online)	1557-3125
ISSN	1541-7786
DOI	10.1158/1541-7786.MCR-22-0111
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Zs.A 5744: Show issues

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Article ; Online: PARPs in lipid metabolism and related diseases.

Szántó, Magdolna / Gupte, Rebecca / Kraus, W Lee / Pacher, Pal / Bai, Peter

Progress in lipid research

2021 Volume 84, Page(s) 101117

Abstract: PARPs and tankyrases (TNKS) represent a family of 17 proteins. PARPs and tankyrases were originally identified as DNA repair factors, nevertheless, recent advances have shed light on their role in lipid metabolism. To date, PARP1, PARP2, PARP3, ... ...

Abstract	PARPs and tankyrases (TNKS) represent a family of 17 proteins. PARPs and tankyrases were originally identified as DNA repair factors, nevertheless, recent advances have shed light on their role in lipid metabolism. To date, PARP1, PARP2, PARP3, tankyrases, PARP9, PARP10, PARP14 were reported to have multi-pronged connections to lipid metabolism. The activity of PARP enzymes is fine-tuned by a set of cholesterol-based compounds as oxidized cholesterol derivatives, steroid hormones or bile acids. In turn, PARPs modulate several key processes of lipid homeostasis (lipotoxicity, fatty acid and steroid biosynthesis, lipoprotein homeostasis, fatty acid oxidation, etc.). PARPs are also cofactors of lipid-responsive nuclear receptors and transcription factors through which PARPs regulate lipid metabolism and lipid homeostasis. PARP activation often represents a disruptive signal to (lipid) metabolism, and PARP-dependent changes to lipid metabolism have pathophysiological role in the development of hyperlipidemia, obesity, alcoholic and non-alcoholic fatty liver disease, type II diabetes and its complications, atherosclerosis, cardiovascular aging and skin pathologies, just to name a few. In this synopsis we will review the evidence supporting the beneficial effects of pharmacological PARP inhibitors in these diseases/pathologies and propose repurposing PARP inhibitors already available for the treatment of various malignancies.
MeSH term(s)	Cholesterol ; Diabetes Mellitus, Type 2 ; Fatty Acids ; Humans ; Lipid Metabolism ; Non-alcoholic Fatty Liver Disease ; Poly(ADP-ribose) Polymerases ; Proto-Oncogene Proteins
Chemical Substances	Fatty Acids ; Proto-Oncogene Proteins ; Cholesterol (97C5T2UQ7J) ; PARP10 protein, human (EC 2.4.2.30) ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30)
Language	English
Publishing date	2021-08-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	282560-0
ISSN	1873-2194 ; 0079-6832 ; 0163-7827
ISSN (online)	1873-2194
ISSN	0079-6832 ; 0163-7827
DOI	10.1016/j.plipres.2021.101117
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Article ; Online: PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes.

Gupte, Rebecca / Liu, Ziying / Kraus, W Lee

Genes & development

2017 Volume 31, Issue 2, Page(s) 101–126

Abstract: The discovery of poly(ADP-ribose) >50 years ago opened a new field, leading the way for the discovery of the poly(ADP-ribose) polymerase (PARP) family of enzymes and the ADP-ribosylation reactions that they catalyze. Although the field was initially ... ...

Abstract	The discovery of poly(ADP-ribose) >50 years ago opened a new field, leading the way for the discovery of the poly(ADP-ribose) polymerase (PARP) family of enzymes and the ADP-ribosylation reactions that they catalyze. Although the field was initially focused primarily on the biochemistry and molecular biology of PARP-1 in DNA damage detection and repair, the mechanistic and functional understanding of the role of PARPs in different biological processes has grown considerably of late. This has been accompanied by a shift of focus from enzymology to a search for substrates as well as the first attempts to determine the functional consequences of site-specific ADP-ribosylation on those substrates. Supporting these advances is a host of methodological approaches from chemical biology, proteomics, genomics, cell biology, and genetics that have propelled new discoveries in the field. New findings on the diverse roles of PARPs in chromatin regulation, transcription, RNA biology, and DNA repair have been complemented by recent advances that link ADP-ribosylation to stress responses, metabolism, viral infections, and cancer. These studies have begun to reveal the promising ways in which PARPs may be targeted therapeutically for the treatment of disease. In this review, we discuss these topics and relate them to the future directions of the field.
MeSH term(s)	Animals ; DNA Repair/genetics ; Enzyme Activation ; Host-Pathogen Interactions ; Humans ; Molecular Biology/trends ; Nicotinamide-Nucleotide Adenylyltransferase/metabolism ; Poly(ADP-ribose) Polymerases/metabolism ; Signal Transduction/genetics ; Transcription, Genetic/genetics
Chemical Substances	Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; Nicotinamide-Nucleotide Adenylyltransferase (EC 2.7.7.1)
Language	English
Publishing date	2017-01-15
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	806684-x
ISSN	1549-5477 ; 0890-9369
ISSN (online)	1549-5477
ISSN	0890-9369
DOI	10.1101/gad.291518.116
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Zs.A 2292: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 54: Show issues

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Article: Nuclear receptors in inflammation control: Repression by GR and beyond

Chinenov, Yurii / Gupte, Rebecca / Rogatsky, Inez

Molecular and cellular endocrinology. 2013 Nov. 5, v. 380, no. 1-2

2013

Abstract: Inflammation is a protective response of organisms to pathogens, irritation or injury. Primary inflammatory sensors activate an array of signaling pathways that ultimately converge upon a few transcription factors such as AP1, NFκB and STATs that in turn ...

Abstract	Inflammation is a protective response of organisms to pathogens, irritation or injury. Primary inflammatory sensors activate an array of signaling pathways that ultimately converge upon a few transcription factors such as AP1, NFκB and STATs that in turn stimulate expression of inflammatory genes to ultimately eradicate infection and repair the damage. A disturbed balance between activation and inhibition of inflammatory pathways can set the stage for chronic inflammation which is increasingly recognized as a key pathogenic component of autoimmune, metabolic, cardiovascular and neurodegenerative disorders. Nuclear receptors (NRs) are a large family of transcription factors many of which are known for their potent anti-inflammatory actions. Activated by small lipophilic ligands, NRs interact with a wide range of transcription factors, cofactors and chromatin-modifying enzymes, assembling numerous cell- and tissue-specific DNA–protein transcriptional regulatory complexes with diverse activities. Here we discuss established and emerging roles and mechanisms by which NRs and, in particular, the glucocorticoid receptor (GR) repress genes encoding cytokines, chemokines and other pro-inflammatory mediators.
Keywords	anti-inflammatory activity ; chemokines ; enzymes ; genes ; glucocorticoid receptors ; inflammation ; neurodegenerative diseases ; pathogens ; signal transduction ; transcription (genetics) ; transcription factor NF-kappa B
Language	English
Dates of publication	2013-1105
Size	p. 55-64.
Publishing place	Elsevier Ireland Ltd
Document type	Article
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2013.04.006
Database	NAL-Catalogue (AGRICOLA)

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Zs.A 1127: Show issues

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Article ; Online: Nuclear receptors in inflammation control: repression by GR and beyond.

Chinenov, Yurii / Gupte, Rebecca / Rogatsky, Inez

Molecular and cellular endocrinology

2013 Volume 380, Issue 1-2, Page(s) 55–64

Abstract	Inflammation is a protective response of organisms to pathogens, irritation or injury. Primary inflammatory sensors activate an array of signaling pathways that ultimately converge upon a few transcription factors such as AP1, NFκB and STATs that in turn stimulate expression of inflammatory genes to ultimately eradicate infection and repair the damage. A disturbed balance between activation and inhibition of inflammatory pathways can set the stage for chronic inflammation which is increasingly recognized as a key pathogenic component of autoimmune, metabolic, cardiovascular and neurodegenerative disorders. Nuclear receptors (NRs) are a large family of transcription factors many of which are known for their potent anti-inflammatory actions. Activated by small lipophilic ligands, NRs interact with a wide range of transcription factors, cofactors and chromatin-modifying enzymes, assembling numerous cell- and tissue-specific DNA-protein transcriptional regulatory complexes with diverse activities. Here we discuss established and emerging roles and mechanisms by which NRs and, in particular, the glucocorticoid receptor (GR) repress genes encoding cytokines, chemokines and other pro-inflammatory mediators.
MeSH term(s)	Animals ; Base Sequence ; Binding Sites ; Chemokines/genetics ; Chemokines/metabolism ; Consensus Sequence ; Epigenesis, Genetic ; Glucocorticoids/physiology ; Humans ; Inflammation/genetics ; Inflammation/metabolism ; Protein Binding ; Receptors, Cytoplasmic and Nuclear/physiology ; Receptors, Glucocorticoid/physiology ; Transcription, Genetic
Chemical Substances	Chemokines ; Glucocorticoids ; Receptors, Cytoplasmic and Nuclear ; Receptors, Glucocorticoid
Language	English
Publishing date	2013-04-26
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2013.04.006
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Article ; Online: Glucocorticoid receptor coordinates transcription factor-dominated regulatory network in macrophages.

Chinenov, Yurii / Coppo, Maddalena / Gupte, Rebecca / Sacta, Maria A / Rogatsky, Inez

BMC genomics

2014 Volume 15, Page(s) 656

Abstract: Background: Inflammation triggered by infection or injury is tightly controlled by glucocorticoid hormones which signal via a dedicated transcription factor, the Glucocorticoid Receptor (GR), to regulate hundreds of genes. However, the hierarchy of ... ...

Abstract	Background: Inflammation triggered by infection or injury is tightly controlled by glucocorticoid hormones which signal via a dedicated transcription factor, the Glucocorticoid Receptor (GR), to regulate hundreds of genes. However, the hierarchy of transcriptional responses to GR activation and the molecular basis of their oftentimes non-linear dynamics are not understood. Results: We investigated early glucocorticoid-driven transcriptional events in macrophages, a cell type highly responsive to both pro- and anti-inflammatory stimuli. Using whole transcriptome analyses in resting and acutely lipopolysaccharide (LPS)-stimulated macrophages, we show that early GR target genes form dense networks with the majority of control nodes represented by transcription factors. The expression dynamics of several glucocorticoid-responsive genes are consistent with feed forward loops (FFL) and coincide with rapid GR recruitment. Notably, GR binding sites in genes encoding members of the KLF transcription factor family colocalize with KLF binding sites. Moreover, our gene expression, transcription factor binding and computational data are consistent with the existence of the GR-KLF9-KLF2 incoherent FFL. Analysis of LPS-downregulated genes revealed striking enrichment in multimerized Zn-fingers- and KRAB domain-containing proteins known to bind nucleic acids and repress transcription by propagating heterochromatin. This raises an intriguing possibility that an increase in chromatin accessibility in inflammatory macrophages results from broad downregulation of negative chromatin remodelers. Conclusions: Pro- and anti-inflammatory stimuli alter the expression of a vast array of transcription factors and chromatin remodelers. By regulating multiple transcription factors, which propagate the initial hormonal signal, GR acts as a coordinating hub in anti-inflammatory responses. As several KLFs promote the anti-inflammatory program in macrophages, we propose that GR and KLFs functionally cooperate to curb inflammation.
MeSH term(s)	Animals ; Computational Biology ; Dexamethasone/pharmacology ; Down-Regulation/drug effects ; Gene Expression Profiling ; Gene Regulatory Networks/drug effects ; Glucocorticoids/pharmacology ; Kinetics ; Lipopolysaccharides/pharmacology ; Macrophages/cytology ; Macrophages/drug effects ; Macrophages/metabolism ; Mice ; Models, Biological ; Receptors, Glucocorticoid/metabolism ; Signal Transduction/drug effects ; Transcription Factors/metabolism ; Transcriptional Activation/drug effects
Chemical Substances	Glucocorticoids ; Lipopolysaccharides ; Receptors, Glucocorticoid ; Transcription Factors ; Dexamethasone (7S5I7G3JQL)
Language	English
Publishing date	2014-08-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1471-2164
ISSN (online)	1471-2164
DOI	10.1186/1471-2164-15-656
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Article ; Online: Glucocorticoid receptor represses proinflammatory genes at distinct steps of the transcription cycle.

Gupte, Rebecca / Muse, Ginger W / Chinenov, Yurii / Adelman, Karen / Rogatsky, Inez

Proceedings of the National Academy of Sciences of the United States of America

2013 Volume 110, Issue 36, Page(s) 14616–14621

Abstract: Widespread anti-inflammatory actions of glucocorticoid hormones are mediated by the glucocorticoid receptor (GR), a ligand-dependent transcription factor of the nuclear receptor superfamily. In conjunction with its corepressor GR-interacting protein-1 ( ... ...

Abstract	Widespread anti-inflammatory actions of glucocorticoid hormones are mediated by the glucocorticoid receptor (GR), a ligand-dependent transcription factor of the nuclear receptor superfamily. In conjunction with its corepressor GR-interacting protein-1 (GRIP1), GR tethers to the DNA-bound activator protein-1 and NF-κB and represses transcription of their target proinflammatory cytokine genes. However, these target genes fall into distinct classes depending on the step of the transcription cycle that is rate-limiting for their activation: Some are controlled through RNA polymerase II (PolII) recruitment and initiation, whereas others undergo signal-induced release of paused elongation complexes into productive RNA synthesis. Whether these genes are differentially regulated by GR is unknown. Here we report that, at the initiation-controlled inflammatory genes in primary macrophages, GR inhibited LPS-induced PolII occupancy. In contrast, at the elongation-controlled genes, GR did not affect PolII recruitment or transcription initiation but promoted, in a GRIP1-dependent manner, the accumulation of the pause-inducing negative elongation factor. Consistently, GR-dependent repression of elongation-controlled genes was abolished specifically in negative elongation factor-deficient macrophages. Thus, GR:GRIP1 use distinct mechanisms to repress inflammatory genes at different stages of the transcription cycle.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Bone Marrow Cells/cytology ; Bone Marrow Cells/drug effects ; Bone Marrow Cells/metabolism ; Cells, Cultured ; Cytokines/genetics ; Dexamethasone/pharmacology ; Gene Expression Regulation ; Immunoblotting ; Inflammation Mediators/metabolism ; Lipopolysaccharides/pharmacology ; Macrophages/cytology ; Macrophages/drug effects ; Macrophages/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NF-kappa B/pharmacology ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Positive Transcriptional Elongation Factor B/genetics ; Positive Transcriptional Elongation Factor B/metabolism ; RNA Polymerase II/metabolism ; Receptors, Glucocorticoid/genetics ; Receptors, Glucocorticoid/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transcription, Genetic/genetics
Chemical Substances	Adaptor Proteins, Signal Transducing ; Cytokines ; Grip1 protein, mouse ; Inflammation Mediators ; Lipopolysaccharides ; NF-kappa B ; Nerve Tissue Proteins ; Receptors, Glucocorticoid ; Transcription Factors ; negative elongation factor ; Dexamethasone (7S5I7G3JQL) ; Positive Transcriptional Elongation Factor B (EC 2.7.11.-) ; RNA Polymerase II (EC 2.7.7.-)
Language	English
Publishing date	2013-08-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1309898110
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Zs.A 1148: Show issues

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Article ; Online: PARP-1 Controls the Adipogenic Transcriptional Program by PARylating C/EBPβ and Modulating Its Transcriptional Activity.

Luo, Xin / Ryu, Keun Woo / Kim, Dae-Seok / Nandu, Tulip / Medina, Carlos J / Gupte, Rebecca / Gibson, Bryan A / Soccio, Raymond E / Yu, Yonghao / Gupta, Rana K / Kraus, W Lee

Molecular cell

2017 Volume 65, Issue 2, Page(s) 260–271

Abstract: Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification of proteins mediated by PARP family members, such as PARP-1. Although PARylation has been studied extensively, few examples of definitive biological roles for site-specific ... ...

Abstract	Poly(ADP-ribosyl)ation (PARylation) is a post-translational modification of proteins mediated by PARP family members, such as PARP-1. Although PARylation has been studied extensively, few examples of definitive biological roles for site-specific PARylation have been reported. Here we show that C/EBPβ, a key pro-adipogenic transcription factor, is PARylated by PARP-1 on three amino acids in a conserved regulatory domain. PARylation at these sites inhibits C/EBPβ's DNA binding and transcriptional activities and attenuates adipogenesis in various genetic and cell-based models. Interestingly, PARP-1 catalytic activity drops precipitously during the first 48 hr of differentiation, corresponding to a release of C/EBPβ from PARylation-mediated inhibition. This promotes the binding of C/EBPβ at enhancers controlling the expression of adipogenic target genes and continued differentiation. Depletion or chemical inhibition of PARP-1, or mutation of the PARylation sites on C/EBPβ, enhances these early adipogenic events. Collectively, our results provide a clear example of how site-specific PARylation drives biological outcomes.
MeSH term(s)	3T3-L1 Cells ; Adipocytes/drug effects ; Adipocytes/enzymology ; Adipogenesis/drug effects ; Animals ; Binding Sites ; CCAAT-Enhancer-Binding Protein-beta/genetics ; CCAAT-Enhancer-Binding Protein-beta/metabolism ; DNA/genetics ; DNA/metabolism ; Embryonic Stem Cells/drug effects ; Embryonic Stem Cells/enzymology ; Genotype ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mutation ; NIH 3T3 Cells ; Phenotype ; Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors ; Poly (ADP-Ribose) Polymerase-1/deficiency ; Poly (ADP-Ribose) Polymerase-1/genetics ; Poly (ADP-Ribose) Polymerase-1/metabolism ; Poly Adenosine Diphosphate Ribose/metabolism ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Protein Binding ; Protein Domains ; Protein Processing, Post-Translational ; RNA Interference ; Signal Transduction ; Time Factors ; Transcription, Genetic/drug effects ; Transcriptional Activation ; Transfection
Chemical Substances	CCAAT-Enhancer-Binding Protein-beta ; Cebpb protein, mouse ; Poly(ADP-ribose) Polymerase Inhibitors ; Poly Adenosine Diphosphate Ribose (26656-46-2) ; DNA (9007-49-2) ; Parp1 protein, mouse (EC 2.4.2.30) ; Poly (ADP-Ribose) Polymerase-1 (EC 2.4.2.30)
Language	English
Publishing date	2017-01-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2016.11.015
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Zs.A 5055: Show issues

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Article ; Online: Role of transcriptional coregulator GRIP1 in the anti-inflammatory actions of glucocorticoids.

Chinenov, Yurii / Gupte, Rebecca / Dobrovolna, Jana / Flammer, Jamie R / Liu, Bill / Michelassi, Francesco E / Rogatsky, Inez

Proceedings of the National Academy of Sciences of the United States of America

2012 Volume 109, Issue 29, Page(s) 11776–11781

Abstract: Inhibition of cytokine gene expression by the hormone-activated glucocorticoid receptor (GR) is the key component of the anti-inflammatory actions of glucocorticoids, yet the underlying molecular mechanisms remain obscure. Here we report that ... ...

Abstract	Inhibition of cytokine gene expression by the hormone-activated glucocorticoid receptor (GR) is the key component of the anti-inflammatory actions of glucocorticoids, yet the underlying molecular mechanisms remain obscure. Here we report that glucocorticoid repression of cytokine genes in primary macrophages is mediated by GR-interacting protein (GRIP)1, a transcriptional coregulator of the p160 family, which is recruited to the p65-occupied genomic NFκB-binding sites in conjunction with liganded GR. We created a mouse strain enabling a conditional hematopoietic cell-restricted deletion of GRIP1 in adult animals. In this model, GRIP1 depletion in macrophages attenuated in a dose-dependent manner repression of NFκB target genes by GR irrespective of the upstream Toll-like receptor pathway responsible for their activation. Furthermore, genome-wide transcriptome analysis revealed a broad derepression of lipopolysaccharide (LPS)-induced glucocorticoid-sensitive targets in GRIP1-depleted macrophages without affecting their activation by LPS. Consistently, conditional GRIP1-deficient mice were sensitized, relative to the wild type, to a systemic inflammatory challenge developing characteristic signs of LPS-induced shock. Thus, by serving as a GR corepressor, GRIP1 facilitates the anti-inflammatory effects of glucocorticoids in vivo.
MeSH term(s)	Adaptor Proteins, Signal Transducing/deficiency ; Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/immunology ; Animals ; Anti-Inflammatory Agents/immunology ; Cells, Cultured ; Chromatin Immunoprecipitation ; Cytokines/antagonists & inhibitors ; Gene Expression Profiling ; Gene Expression Regulation/immunology ; Glucocorticoids/immunology ; Immunoblotting ; Macrophages/immunology ; Mice ; Mice, Transgenic ; Nerve Tissue Proteins/deficiency ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/immunology ; Real-Time Polymerase Chain Reaction ; Receptors, Glucocorticoid/immunology ; Sequence Analysis, RNA ; Survival Analysis ; Transcription Factor RelA/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; Anti-Inflammatory Agents ; Cytokines ; Glucocorticoids ; Grip1 protein, mouse ; Nerve Tissue Proteins ; Receptors, Glucocorticoid ; Transcription Factor RelA
Language	English
Publishing date	2012-07-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1206059109
Database	MEDical Literature Analysis and Retrieval System OnLINE

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