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

Jana Reinemund, Kerstin Seidel, Ulrike M. 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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1795-1805
Number of pages11
JournalBiochemical Pharmacology
Volume77
Issue number12
DOIs
StatePublished - Jun 15 2009

Fingerprint

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

Keywords

  • Angiotensin AT2 receptor
  • ATBP genes
  • Cardiovascular pathophysiology
  • PARP-1
  • Promoter
  • Renin-angiotensin system (RAS)

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

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 M.; 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.

In: Biochemical Pharmacology, Vol. 77, No. 12, 15.06.2009, p. 1795-1805.

Research output: Contribution to journalArticle

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, vol. 77, no. 12, pp. 1795-1805. https://doi.org/10.1016/j.bcp.2009.02.025
Reinemund, Jana ; Seidel, Kerstin ; Steckelings, Ulrike M. ; 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. In: Biochemical Pharmacology. 2009 ; Vol. 77, No. 12. pp. 1795-1805.
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AU - Steckelings, Ulrike M.

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

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