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Titolo:
Transcriptional mechanism of protein kinase c-induced isoform-specific expression of the gene for endothelin-converting enzyme-1 in human endothelialcells
Autore:
Orzechowski, HD; Gunther, A; Menzel, S; Zimmermann, A; Funke-Kaiser, H; Real, R; Subkowski, T; Zollmann, FS; Paul, M;
Indirizzi:
Free Univ Berlin, Benjamin Franklin Med Ctr, Inst Clin Pharmacol & Toxicol, D-14195 Berlin, Germany Free Univ Berlin Berlin Germany D-14195 Toxicol, D-14195 Berlin, Germany BASF AG, Main Lab, Ludwigshafen, Germany BASF AG Ludwigshafen GermanyBASF AG, Main Lab, Ludwigshafen, Germany
Titolo Testata:
MOLECULAR PHARMACOLOGY
fascicolo: 6, volume: 60, anno: 2001,
pagine: 1332 - 1342
SICI:
0026-895X(200112)60:6<1332:TMOPKC>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
MESSENGER-RNA; IN-VIVO; ECE-1; ACTIVATION; PROMOTER; CLONING; METALLOPROTEASE; ATHEROSCLEROSIS; ANGIOGENESIS; RAT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
40
Recensione:
Indirizzi per estratti:
Indirizzo: Paul, M Free Univ Berlin, Benjamin Franklin Med Ctr, Inst Clin Pharmacol &Toxicol, Garystr 5, D-14195 Berlin, Germany Free Univ Berlin Garystr 5 Berlin Germany D-14195 Berlin, Germany
Citazione:
H.D. Orzechowski et al., "Transcriptional mechanism of protein kinase c-induced isoform-specific expression of the gene for endothelin-converting enzyme-1 in human endothelialcells", MOLEC PHARM, 60(6), 2001, pp. 1332-1342

Abstract

Isoform-specific expression of endothelin-converting enzyme (ECE)-1, the major big endothelin-processing enzyme, is controlled by alternative promoters. Signaling pathways and transcriptional mechanisms of ECE-1 mRNA expression are largely unknown. To investigate ECE-1 isoform expression after protein kinase C (PKC) activation, we used phorbol 12-myristate 13-acetate (PMA) to stimulate primary cultured human umbilical vein endothelial cells and the related EA.hy926 cell line. ECE-1a mRNA was up-regulated (approximately3-fold), whereas mRNA of alternative isoforms (b, c, and d) was unchanged,which was confirmed on the protein level. PMA effects on mRNA expression were suppressed by the PKC inhibitors H-7 and Calphostin C. Because increased ECE-1a expression was preceded by induction of the transcription factor Ets-1, we performed gel shift assays and demonstrated specific DNA/protein interactions involving the ETS binding motif GGAA. Luciferase reporter assays showed that PMA induced ECE-1a promoter activity about 2.5-fold in EA.hy926 cells. Similarly, coexpression of Ets-1 protein resulted in a dose-dependent increase in ECE-1a promoter activity (more than 8-fold). Using gel shift assays and mutation analysis, we identified two tandemly arranged Ets-1 binding sites (EBS) at -638 and -658, respectively, that are involved in transcriptional activation of the ECE-1a promoter by PMA or Ets-1. Moreover, we also found evidence for binding of a transcriptional repressor to EBS -638. The inhibitor of mitogen-activated protein kinase kinase, PD98059, inhibited PMA effects on ECE-1 a mRNA expression and promoter activity, respectively. Our results provide the first detailed analysis of signaling pathways and transcriptional mechanisms involved in isoform-specific ECE-1 gene expression.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 02/10/20 alle ore 01:41:27