INHIBITION OF PROLACTIN GENE-TRANSCRIPTION BY TRANSFORMING GROWTH-FACTOR-BETA IN GH3 CELLS

Transforming growth factor-beta (TGF-beta) is a member of a large family of growth factors, several of which regulate pituitary function. TGF-beta has recently been reported to reduce PRL production by GH4 cells. We have examined the effect of TGF-beta on PRL gene expression in rat pituitary tumor GH3 cells. TGF-beta-1 or TGF-beta-2 reduced both basal and Ca2+-stimulated PRL mRNA levels. This inhibition was specific, as the mRNA levels for GH, glucose-regulated protein 78, and histone-3 were unaffected by TGF-beta. Inhibition of PRL gene expression by TGF-beta was dose dependent in the range of 0.5-10 ng/ml. TGF-beta inhibited run-on PRL gene transcription in nuclei from treated cells to the same extent that it reduced PRL mRNA levels, indicating a transcriptional mechanism of action. However, TGF-beta did not affect Pit-1 mRNA levels or run-on transcription of the Pit-1 gene. Thus, TGF-beta does not appear to act through modification of Pit-1 gene expression. The PRL promotor contains two regions of homology, with a consensus sequence found in the promotors of other TGF-beta-inhibited genes. These findings are consistent with other studies that have demonstrated transcriptional repression by TGF-beta. The potency and specificity of the effects of TGF-beta on PRL gene expression suggest that it may be a physiological regulator of lactotroph function.