ENDOTHELIN-1 IS A POTENT SURVIVAL FACTOR FOR C-MYC-DEPENDENT APOPTOSIS

Many vertebrate cells are resistant to apoptotic stimuli, whose variet y and the mechanisms involved are not fully understood. Endothelin-1 i s an endothelium-derived vasoactive peptide that mediates many physiol ogical functions, such as vasoconstriction and cell proliferation. Der egulated expression of c-Myc induces apoptosis in serum-deprived fibro blasts. Using a panel of isogenic fibroblast cell lines with different ial c-myc expression levels, we demonstrate that low doses of endothel in-1 protect fibroblasts against serum deprivation-induced apoptosis, which occurs through a c-Myc-dependent process. The endothelin-1-induc ed cell survival was mediated by the ETA receptor and was not linked t o the ability of endothelin-1 to induce cell proliferation. The surviv al function of endothelin-1 was abrogated by inhibiting the mitogen-ac tivated protein kinase pathway. These results demonstrate a hitherto u nappreciated role of endothelin-1 as a potent survival factor for c-My c-dependent apoptosis, a process mediated by the ETA receptor and the mitogen-activated protein kinase pathway.