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(Circulation Research. 2006;99:1355.)
© 2006 American Heart Association, Inc.

Molecular Medicine

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

Jan H. Schefe, Mario Menk, Jana Reinemund, Karin Effertz, Robin M. Hobbs, Pier Paolo Pandolfi, Patricia Ruiz, Thomas Unger^*, Heiko Funke-Kaiser^*

From the Center for Cardiovascular Research/Institute of Pharmacology (J.H.S., M.M., J.R., T.U., H.F.-K.), Department of Anesthesiology and Intensive Care Medicine (M.M.), and Center for Cardiovascular Research (K.E., P.R.), Charité–Universitätsmedizin Berlin, Germany; Max Planck Institute for Molecular Genetics (K.E., P.R.), Berlin, Germany; and Cancer Biology and Genetics Program (R.M.H., P.P.P.), Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York.

Correspondence to Heiko Funke-Kaiser, Center for Cardiovascular Research (CCR)/Institute of Pharmacology, Charité–Universitätsmedizin Berlin, Hessische Strasse 3-4, 10115 Berlin, Germany. E-mail heiko.funke-kaiser{at}charite.de

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 subunit of the phosphatidylinositol-3 kinase (PI3K-p85). 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. 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.

Key Words: renin receptor • PLZF • ChIP • signal transduction

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