RETINOIC ACID ABOLISHES THE CALCITONIN-GENE-RELATED PEPTIDE AUTOCRINESYSTEM IN F9 TERATOCARCINOMA CELLS

Calcitonin gene-related peptide (CGRP), expressed predominantly in F9 embryonal carcinoma cells, is bath a potent chemotactic agent and an a utocrine growth factor for these cells. We analyzed the effect of reti noic acid (RA)-induced differentiation of F9 cells into primitive pari etal endoderm-like cells, on CGRP production and the CGRP responsivene ss of these cells. Poly(A) RNA extracted from F9 cells and analysed by Northern blotting and hybridization with a CGRP probe showed a specif ic band of about 1200 bases corresponding to mature CGRP mRNA. This ba nd was not detected in F9 cells treated for 6 days with RA (differenti ated primitive parietal endoderm-like cells) or in PYS cells (establis hed parietal endoderm-like cell line). During RA-induced differentiati on of F9 cells, CGRP mRNA levels fell within 24 h after treatment and were almost undetectable after 2 days. RA treatment also reduced CGRP secretion by F9 cells; the effect was maximal at 3 days and remained s table thereafter. Similarly RA rapidly reduced adenylate cyclase respo nsiveness to chicken CGRP (cCGRP) and human CGRP (hCGRP). An 80% fall in cAMP release into the culture medium in the presence of CGRP was ob served after 24 h of RA treatment. These results demonstrate that RA r apidly abolishes the CGRP autocrine system involved in the proliferati on of F9 cells, at the same time inducing their differentiation into p rimitive parietal endoderm. They point to the interaction between reti noic acid and growth factors in the regulation of cell proliferation a nd differentiation. (C) 1997 Wiley-Liss, Inc.