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Molecular Endocrinology 12 (2): 172-180
Copyright © 1997 by The Endocrine Society

Endothelin-1 Is a Potent Survival Factor for c-Myc-Dependent Apoptosis

Masayoshi Shichiri, John M. Sedivy, Fumiaki Marumo and Yukio Hirata

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

Many vertebrate cells are resistant to apoptotic stimuli, whose variety and the mechanisms involved are not fully understood. Endothelin-1 is an endothelium-derived vasoactive peptide that mediates many physiological functions, such as vasoconstriction and cell proliferation. Deregulated expression of c-Myc induces apoptosis in serum-deprived fibroblasts. Using a panel of isogenic fibroblast cell lines with differential c-myc expression levels, we demonstrate that low doses of endothelin-1 protect fibroblasts against serum deprivation-induced apoptosis, which occurs through a c-Myc-dependent process. The endothelin-1-induced cell survival was mediated by the ETA receptor and was not linked to the ability of endothelin-1 to induce cell proliferation. The survival function of endothelin-1 was abrogated by inhibiting the mitogen-activated protein kinase pathway. These results demonstrate a hitherto unappreciated role of endothelin-1 as a potent survival factor for c-Myc-dependent apoptosis, a process mediated by the ETA receptor and the mitogen-activated protein kinase pathway.




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