Biphasic regulation of the preproendothelin-1 gene by c-myc.
Endothelin-1 (ET-1), a potent vasoconstrictive/mitogenic peptide originally isolated from vascular endothelium, stimulates the expression of immediate early response genes such as c-myc. The c-myc protooncogene participates in regulating the cascade of events that follow mitogenic stimulation of quiescent cells. Using a panel of isogenic fibroblast cell lines with differential c-myc expression levels (obtained by disrupting one c-myc gene copy with targeted homologous recombination and subsequently stably transfecting the heterozygous cells with an exogenous c-myc transgene), we demonstrate that c-Myc protein regulates ET-1 gene transcription in a biphasic fashion: as an activator at low concentrations and as a repressor at high concentrations. Using rat endothelial cells treated with antisense c-myc oligodeoxynucleotides, we also show that c-myc regulates ET-1 synthesis and secretion in a biphasic manner. The present report, therefore, demonstrates the existence of a signal transduction pathway that regulates the synthesis and secretion of ET-1 via the immediate early transcription factor, c-Myc.
Shichiri
M
M
Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan. mshichiri.med2@med.tmd.ac.jp
Adachi
S
S
Sedivy
J M
JM
Marumo
F
F
Hirata
Y
Y
D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D019332:Endothelin-1; D016232:Endothelins / Q000235:genetics*; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D005347:Fibroblasts; D017353:Gene Deletion; D005786:Gene Expression Regulation; D016259:Genes, myc; D011401:Promoter Regions, Genetic / Q000502:physiology; D011498:Protein Precursors / Q000235:genetics*; D051381:Rats
D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors