Endothelin-1 is a potent survival factor for c-Myc-dependent apoptosis.
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 ET(A) 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 ET(A) receptor and the mitogen-activated protein kinase pathway.
Shichiri
M
M
Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan. mshichiri.med2@med.tmd.ac.jp
Sedivy
J M
JM
Marumo
F
F
Hirata
Y
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016895:Culture Media, Serum-Free; D019332:Endothelin-1 / Q000494:pharmacology*; D005347:Fibroblasts; D005786:Gene Expression Regulation / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D051381:Rats; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology
D016895:Culture Media, Serum-Free; D019332:Endothelin-1; D016271:Proto-Oncogene Proteins c-myc; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D017871:Calcium-Calmodulin-Dependent Protein Kinases