A novel signal transduction cascade involving direct physical interaction of the renin/prorenin receptor with the transcription factor promyelocytic zinc finger protein Journal Article
| Authors: | Schefe, J. H.; Menk, M.; Reinemund, J.; Effertz, K.; Hobbs, R. M.; Pandolfi, P. P.; Ruiz, P.; Unger, T.; Funke-Kaiser, H. |
| Article Title: | A novel signal transduction cascade involving direct physical interaction of the renin/prorenin receptor with the transcription factor promyelocytic zinc finger protein |
| Abstract: | 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 p85α subunit of the phosphatidylinositol-3 kinase (PI3K-p85α). 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-p85α. 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. © 2006 American Heart Association, Inc. |
| Keywords: | signal transduction; controlled study; protein expression; human cell; promoter region; dna-binding proteins; nonhuman; pathophysiology; protein domain; protein function; animal cell; animals; mice; mice, knockout; carboxy terminal sequence; protein protein interaction; transcription initiation; cell line; small interfering rna; transcription factor; neurons; hela cells; phosphatidylinositol 3 kinase; transcription factors; kidney; transcription regulation; cell strain hek293; rna, messenger; chromatin immunoprecipitation; nucleotide sequence; rat; protein transport; 1-phosphatidylinositol 3-kinase; ligand; epithelial cells; cytoplasm; active transport, cell nucleus; neuroglia; dimerization; cell nucleus; receptor; negative feedback; site directed mutagenesis; two hybrid system; gel mobility shift assay; zinc finger protein; heart muscle cell; regulator protein; receptors, cell surface; transcription initiation site; plzf; intracellular membranes; protein p85; renin-angiotensin system; promoter regions (genetics); chip; renin receptor; promyelocytic zinc finger protein; prorenin; renin; renin prorenin receptor; vacuolar proton-translocating atpases |
| Journal Title: | Circulation Research |
| Volume: | 99 |
| Issue: | 12 |
| ISSN: | 0009-7330 |
| Publisher: | Lippincott Williams & Wilkins |
| Date Published: | 2006-12-01 |
| Start Page: | 1355 |
| End Page: | 1366 |
| Language: | English |
| DOI: | 10.1161/01.RES.0000251700.00994.0d |
| PUBMED: | 17082479 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 147" - "Export Date: 4 June 2012" - "CODEN: CIRUA" - "Molecular Sequence Numbers: GENBANK: GI21325928, GI37546587;" - "Source: Scopus" |
