Poly(ADP-ribose) polymerase-1 (PARP-1) transcriptionally regulates angiotensin AT2 receptor (AT2R) and AT2R binding protein (ATBP) genes

Jana Reinemund, Kerstin Seidel, Ulrike Muscha Steckelings, Daniela Zaade, Sabrina Klare, Franziska Rompe, Marlen Katerbaum, Jens Schacherl, Yaosi Li, Mario Menk, Jan H Schefe, Petra Goldin-Lang, Csaba Szabo, Gabor Olah, Thomas Unger, Heiko Funke-Kaiser

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

The renin-angiotensin system (RAS) plays a crucial role in cardiovascular and neuronal (patho-)physiology. The angiotensin AT2 receptor (AT2R) seems to counteract the proinflammatory, prohypertrophic and profibrotic actions of the AT1 receptor. Recently, we identified a novel protein, termed "AT2R binding protein" (ATBP/ATIP) which seems essential for AT2R-mediated growth inhibition. Poly(ADP-ribose) polymerase-1 (PARP-1) can act as a nuclear integrator of angiotensin II-mediated cell signalling, and has been implicated in the pathogenesis of cardiovascular and neuronal disease. In this study, promoters of human AT2R and ATIP1 were cloned and two transcriptional start sites in the ATIP1 promoter were identified whereas only one was detected in the AT2R promoter. Promoter assays indicated that the exon 1-intron 1 region of AT2R is necessary and sufficient for AT2R promoter activity. Inverse cloning experiments indicated that this regulatory region is a promoter but not an enhancer element implicating (a) further start site(s) in this region. Consistently, the exon 1-intron 1 region of AT2R was shown to tether the basal transcriptional machinery. Overexpression, pharmacological inhibition and ablation of PARP demonstrated that PARP-1 activates the ATIP1 gene but represses the AT2R on promoter and mRNA levels in vitro, and in brain tissue in vivo. Additional experiments indicated that AT2R activation does not modulate PARP-1 transcript levels but increases AT2R promoter activity, thereby creating a positive feedback mechanism. Our results demonstrate that PARP-1 acts as novel node within the RAS network based on its ability to regulate downstream targets such as AT2R and its adapter protein ATBP.
OriginalsprogEngelsk
TidsskriftBiochemical Pharmacology
Vol/bind77
Udgave nummer12
Sider (fra-til)1795-805
Antal sider11
ISSN0006-2952
DOI
StatusUdgivet - 2009
Udgivet eksterntJa

Fingeraftryk

Angiotensin Type 2 Receptor
Poly(ADP-ribose) Polymerases
Carrier Proteins
Genes
Angiotensins
Renin-Angiotensin System
Renin
Protein Binding
Introns
Exons
Cell signaling
Cloning
Nucleic Acid Regulatory Sequences
Physiology
Ablation
Angiotensin II
Machinery
Organism Cloning
Assays
Brain

Citer dette

Reinemund, Jana ; Seidel, Kerstin ; Steckelings, Ulrike Muscha ; Zaade, Daniela ; Klare, Sabrina ; Rompe, Franziska ; Katerbaum, Marlen ; Schacherl, Jens ; Li, Yaosi ; Menk, Mario ; Schefe, Jan H ; Goldin-Lang, Petra ; Szabo, Csaba ; Olah, Gabor ; Unger, Thomas ; Funke-Kaiser, Heiko. / Poly(ADP-ribose) polymerase-1 (PARP-1) transcriptionally regulates angiotensin AT2 receptor (AT2R) and AT2R binding protein (ATBP) genes. I: Biochemical Pharmacology. 2009 ; Bind 77, Nr. 12. s. 1795-805.
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title = "Poly(ADP-ribose) polymerase-1 (PARP-1) transcriptionally regulates angiotensin AT2 receptor (AT2R) and AT2R binding protein (ATBP) genes",
abstract = "The renin-angiotensin system (RAS) plays a crucial role in cardiovascular and neuronal (patho-)physiology. The angiotensin AT2 receptor (AT2R) seems to counteract the proinflammatory, prohypertrophic and profibrotic actions of the AT1 receptor. Recently, we identified a novel protein, termed {"}AT2R binding protein{"} (ATBP/ATIP) which seems essential for AT2R-mediated growth inhibition. Poly(ADP-ribose) polymerase-1 (PARP-1) can act as a nuclear integrator of angiotensin II-mediated cell signalling, and has been implicated in the pathogenesis of cardiovascular and neuronal disease. In this study, promoters of human AT2R and ATIP1 were cloned and two transcriptional start sites in the ATIP1 promoter were identified whereas only one was detected in the AT2R promoter. Promoter assays indicated that the exon 1-intron 1 region of AT2R is necessary and sufficient for AT2R promoter activity. Inverse cloning experiments indicated that this regulatory region is a promoter but not an enhancer element implicating (a) further start site(s) in this region. Consistently, the exon 1-intron 1 region of AT2R was shown to tether the basal transcriptional machinery. Overexpression, pharmacological inhibition and ablation of PARP demonstrated that PARP-1 activates the ATIP1 gene but represses the AT2R on promoter and mRNA levels in vitro, and in brain tissue in vivo. Additional experiments indicated that AT2R activation does not modulate PARP-1 transcript levels but increases AT2R promoter activity, thereby creating a positive feedback mechanism. Our results demonstrate that PARP-1 acts as novel node within the RAS network based on its ability to regulate downstream targets such as AT2R and its adapter protein ATBP.",
author = "Jana Reinemund and Kerstin Seidel and Steckelings, {Ulrike Muscha} and Daniela Zaade and Sabrina Klare and Franziska Rompe and Marlen Katerbaum and Jens Schacherl and Yaosi Li and Mario Menk and Schefe, {Jan H} and Petra Goldin-Lang and Csaba Szabo and Gabor Olah and Thomas Unger and Heiko Funke-Kaiser",
year = "2009",
doi = "10.1016/j.bcp.2009.02.025",
language = "English",
volume = "77",
pages = "1795--805",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier",
number = "12",

}

Reinemund, J, Seidel, K, Steckelings, UM, Zaade, D, Klare, S, Rompe, F, Katerbaum, M, Schacherl, J, Li, Y, Menk, M, Schefe, JH, Goldin-Lang, P, Szabo, C, Olah, G, Unger, T & Funke-Kaiser, H 2009, 'Poly(ADP-ribose) polymerase-1 (PARP-1) transcriptionally regulates angiotensin AT2 receptor (AT2R) and AT2R binding protein (ATBP) genes', Biochemical Pharmacology, bind 77, nr. 12, s. 1795-805. https://doi.org/10.1016/j.bcp.2009.02.025

Poly(ADP-ribose) polymerase-1 (PARP-1) transcriptionally regulates angiotensin AT2 receptor (AT2R) and AT2R binding protein (ATBP) genes. / Reinemund, Jana; Seidel, Kerstin; Steckelings, Ulrike Muscha; Zaade, Daniela; Klare, Sabrina; Rompe, Franziska; Katerbaum, Marlen; Schacherl, Jens; Li, Yaosi; Menk, Mario; Schefe, Jan H; Goldin-Lang, Petra; Szabo, Csaba; Olah, Gabor; Unger, Thomas; Funke-Kaiser, Heiko.

I: Biochemical Pharmacology, Bind 77, Nr. 12, 2009, s. 1795-805.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Poly(ADP-ribose) polymerase-1 (PARP-1) transcriptionally regulates angiotensin AT2 receptor (AT2R) and AT2R binding protein (ATBP) genes

AU - Reinemund, Jana

AU - Seidel, Kerstin

AU - Steckelings, Ulrike Muscha

AU - Zaade, Daniela

AU - Klare, Sabrina

AU - Rompe, Franziska

AU - Katerbaum, Marlen

AU - Schacherl, Jens

AU - Li, Yaosi

AU - Menk, Mario

AU - Schefe, Jan H

AU - Goldin-Lang, Petra

AU - Szabo, Csaba

AU - Olah, Gabor

AU - Unger, Thomas

AU - Funke-Kaiser, Heiko

PY - 2009

Y1 - 2009

N2 - The renin-angiotensin system (RAS) plays a crucial role in cardiovascular and neuronal (patho-)physiology. The angiotensin AT2 receptor (AT2R) seems to counteract the proinflammatory, prohypertrophic and profibrotic actions of the AT1 receptor. Recently, we identified a novel protein, termed "AT2R binding protein" (ATBP/ATIP) which seems essential for AT2R-mediated growth inhibition. Poly(ADP-ribose) polymerase-1 (PARP-1) can act as a nuclear integrator of angiotensin II-mediated cell signalling, and has been implicated in the pathogenesis of cardiovascular and neuronal disease. In this study, promoters of human AT2R and ATIP1 were cloned and two transcriptional start sites in the ATIP1 promoter were identified whereas only one was detected in the AT2R promoter. Promoter assays indicated that the exon 1-intron 1 region of AT2R is necessary and sufficient for AT2R promoter activity. Inverse cloning experiments indicated that this regulatory region is a promoter but not an enhancer element implicating (a) further start site(s) in this region. Consistently, the exon 1-intron 1 region of AT2R was shown to tether the basal transcriptional machinery. Overexpression, pharmacological inhibition and ablation of PARP demonstrated that PARP-1 activates the ATIP1 gene but represses the AT2R on promoter and mRNA levels in vitro, and in brain tissue in vivo. Additional experiments indicated that AT2R activation does not modulate PARP-1 transcript levels but increases AT2R promoter activity, thereby creating a positive feedback mechanism. Our results demonstrate that PARP-1 acts as novel node within the RAS network based on its ability to regulate downstream targets such as AT2R and its adapter protein ATBP.

AB - The renin-angiotensin system (RAS) plays a crucial role in cardiovascular and neuronal (patho-)physiology. The angiotensin AT2 receptor (AT2R) seems to counteract the proinflammatory, prohypertrophic and profibrotic actions of the AT1 receptor. Recently, we identified a novel protein, termed "AT2R binding protein" (ATBP/ATIP) which seems essential for AT2R-mediated growth inhibition. Poly(ADP-ribose) polymerase-1 (PARP-1) can act as a nuclear integrator of angiotensin II-mediated cell signalling, and has been implicated in the pathogenesis of cardiovascular and neuronal disease. In this study, promoters of human AT2R and ATIP1 were cloned and two transcriptional start sites in the ATIP1 promoter were identified whereas only one was detected in the AT2R promoter. Promoter assays indicated that the exon 1-intron 1 region of AT2R is necessary and sufficient for AT2R promoter activity. Inverse cloning experiments indicated that this regulatory region is a promoter but not an enhancer element implicating (a) further start site(s) in this region. Consistently, the exon 1-intron 1 region of AT2R was shown to tether the basal transcriptional machinery. Overexpression, pharmacological inhibition and ablation of PARP demonstrated that PARP-1 activates the ATIP1 gene but represses the AT2R on promoter and mRNA levels in vitro, and in brain tissue in vivo. Additional experiments indicated that AT2R activation does not modulate PARP-1 transcript levels but increases AT2R promoter activity, thereby creating a positive feedback mechanism. Our results demonstrate that PARP-1 acts as novel node within the RAS network based on its ability to regulate downstream targets such as AT2R and its adapter protein ATBP.

U2 - 10.1016/j.bcp.2009.02.025

DO - 10.1016/j.bcp.2009.02.025

M3 - Journal article

VL - 77

SP - 1795

EP - 1805

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 12

ER -