Identification of the ETA receptor subtype that mediates endothelin induced autocrine proliferation of normal human keratinocytes.
Endothelin-1 has a wide range of pharmacological effects in various tissues and acts as autocrine/paracrine factor. The potential of ET-1 to function as an autocrine growth factor was evaluated in normal human keratinocytes. Radioligand binding studies showed that 125I-ET-1 bound to a single class of high-affinity-binding sites on the surface of the cells. The dissociation constant was 0.045 nM with receptor numbers of 1700 sites/cell. Treatment with serum caused increases in expression of binding sites (3500 sites/cell), with no change in binding affinity. ET-1 stimulated thymidine incorporation in these cells that expressed ET receptors. An ET antagonist selective for the ETA receptor subtype (BQ 123) inhibited DNA synthesis stimulated by ET-1 and reduced the basal growth rate of unstimulated cells. These data suggest that the ET-1 induced DNA synthesis is mediated by ETA receptor subtype and that endogenously produced ET-1 promotes the autocrine proliferation of keratinocytes.
Bagnato
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A
Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, Rome, Italy.
Venuti
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A
Di Castro
V
V
Marcante
M L
ML
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects*; D010456:Peptides, Cyclic / Q000494:pharmacology; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism*
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)