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  A Novel Signal Transduction Cascade Involving Direct Physical Interaction of the Renin/Prorenin Receptor With the Transcription Factor Promyelocytic Zinc Finger Protein

Schefe, J. H., Menk, M., Reinemund, J., Effertz, K., Hobbs, R. M., Pandolfi, P. P., et al. (2006). A Novel Signal Transduction Cascade Involving Direct Physical Interaction of the Renin/Prorenin Receptor With the Transcription Factor Promyelocytic Zinc Finger Protein. Circulation Research, 99(12), 1355-1366. doi:10.1161/01.RES.0000251700.00994.0d.

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Genre: Zeitschriftenartikel
Alternativer Titel : Circ Res

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 Urheber:
Schefe, Jan H., Autor
Menk, Mario, Autor
Reinemund, Jana, Autor
Effertz, Karin, Autor
Hobbs, Robin M., Autor
Pandolfi, Pier Paolo, Autor
Ruiz, Patricia1, Autor
Unger, Thomas, Autor
Funke-Kaiser, Heiko, Autor
Affiliations:
1Max Planck Society, ou_persistent13              

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Schlagwörter: renin receptor; PLZF; ChIP; signal transduction
 Zusammenfassung: A human renin/prorenin receptor (RER) has recently been cloned. To gain insight into the molecular function of the RER, we studied its signal transduction mechanisms. Initially, we found a ubiquitous and intracellular expression pattern of the human RER. Consistently, we observed several transcriptional start sites and a high promoter activity of the human RER. We could identify the transcription factor promyelocytic zinc finger (PLZF) protein as a direct protein interaction partner of the C-terminal domain of the RER by yeast 2-hybrid screening and coimmunoprecipitation. Coimmunoprecipitation experiments also indicated homodimerization of the RER. On activation of the RER by renin, PLZF is translocated into the nucleus and represses transcription of the RER itself, thereby creating a very short negative feedback loop, but activates transcription of the p85{alpha} subunit of the phosphatidylinositol-3 kinase (PI3K-p85{alpha}). Small interfering RNA against the RER abolished these effects. A PLZF cis-element in the RER promoter was identified by site-directed mutagenesis and electrophoretic mobility-shift assay. Renin stimulation caused a 6-fold recruitment of PLZF to this promoter region as shown by chromatin immunoprecipitation. Moreover, renin stimulation of rat H9c2 cardiomyoblasts induced an increase of cell number and a decrease of apoptosis. These effects were partly abolished by PI3K inhibition and completely abrogated by small interfering RNA against PLZF. Finally, experiments in PLZF knockout mice confirmed the role of PLZF as an upstream regulator of RER and PI3K-p85{alpha}. Our data demonstrate the existence of a novel signal transduction pathway involving the ligand renin, RER, and the transcription factor PLZF, which is of physiological and putative pathophysiological relevance.

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Sprache(n): eng - English
 Datum: 2006-12-08
 Publikationsstatus: Erschienen
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: -
 Identifikatoren: eDoc: 312989
DOI: 10.1161/01.RES.0000251700.00994.0d
 Art des Abschluß: -

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Titel: Circulation Research
  Alternativer Titel : Circ Res
Genre der Quelle: Zeitschrift
 Urheber:
Affiliations:
Ort, Verlag, Ausgabe: -
Seiten: - Band / Heft: 99 (12) Artikelnummer: - Start- / Endseite: 1355 - 1366 Identifikator: ISSN: 0009-7330