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Biphasic Regulation of the Preproendothelin-1 Gene by c-myc¹

Endocrine-Hypertension Division, Second Department of Internal Medicine (M.S., S.A., F.M., Y.H.), Tokyo Medical and Dental University, Tokyo 113, Japan; and the Department of Molecular Biology, Cell Biology and Biochemistry (J.M.S.), Brown University, Providence, Rhode Island 02912

Address all correspondence and requests for reprints to: Dr. Masayoshi Shichiri, Second Department of Internal Medicine, Tokyo Medical and Dental University, 1–5-45 Yushima, Bunkyo-ku, Tokyo 113, Japan. E-mail: mshichiri.med2{at}med.tmd.ac.jp

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.

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