LOVASTATIN DECREASES PROLACTIN AND GROWTH-HORMONE GENE-EXPRESSION IN GH(4)C(1) CELLS THROUGH A CAMP-DEPENDENT MECHANISM

The heterotrimeric G protein Gs couples several surface ligand recepto rs to cAMP production, as well as to both growth hormone (GH) and prol actin (PRL) gene expression in pituitary and GH cells. It has been sho wn that constitutively active cts stimulates transient expression of b oth PRL- and GH- chloramphenicol acetyl transferase (CAT) construction s, which indicates that both the PRL and GH promoter regions are under the influence of signal pathways mediated by alpha s. We have previou sly shown that the cholesterol lowering drug lovastatin decreases both the amount of G alpha s subunit in the membrane and the adenylyl cycl ase activity in GH(4)C(1) cells. Thus, we tried to verify whether that decrease in alpha s-levels could affect PRL and GH secretion, as well as the expression of PRL- and OH-CAT constructions. Since the regulat ion of these two genes is dependent on the pituitary specific transcri ption factor Pit-1, the effect of lovastatin on the expression of Pit- 1-CAT constructions was also studied. Our results show that lovastatin decreased the basal expression of these three cAMP-responsive genes i n GH(4)C(1) cells, being partially reversed by the addition of mevalon ate to the culture medium. This effect of lovastatin on the promoter a ctivities of the transfected constructions was also observed in PRL an d GH secretion to the medium, suggesting that this drug produces simil ar changes in the endogenous promoters of both hormones. Moreover, the presence of Iovastatin did not prevent the response to the cAMP activ ator forskolin, indicating that the main effect of this drug could be exerted through upstream adenylyl cyclase. In conclusion, our data ind icate that lovastatin decreases the basal expression of Pit-1 and cons equently of both GH and PRL genes through a mechanism probably mediate d by the decrease of G alpha s levels in the cell membrane. Taken toge ther, these results suggest that the activity of membrane heterotrimer ic G proteins regulates the basal transcription of specific cellular g enes in GH(4)C(1) cells. Moreover the effects of lovastatin may be tak en into account in the study of constitutively endocrine disorders ass ociated with an increased secretion of either PRL or GH. (C) 1997 Else vier Science Ireland Ltd.