Phenotypic switching in GH3 rat pituitary tumor cells: linked expression of growth hormone and another hormonally responsive protein.

From a phenotypically unstable, prolactin-deficient variant of GH3 rat pituitary tumor cells, variants deficient in growth hormone synthesis were isolated at high frequency (about 90%). The rate of synthesis of growth hormone (rGH) and one other hormonally responsive protein, termed p16, was substantially decreased in variant cells. Reduced synthesis of rGH was accompanied by a decrease in cytoplasmic levels of pre-rGH mRNA compared to levels found in wild-type GH3 cells. Although synthesis was decreased, inducibility of rGH and p16 synthesis by dexamethasone was unimpaired. The spontaneous reversion frequency was estimated to be near 4%. The expression of p16 was coordinately regained in an rGH-producing revertant, indicating that the expression of the two proteins is tightly coupled in GH3 cells. It was also found that p16 and p21 (another hormonally responsive protein in GH3 cells whose expression is tightly linked to that of prolactin) were detected at high levels in rat anterior pituitary. These observations suggest that, if growth hormone and p16 are encoded by distinct genes, then during the course of their evolution the two genes have developed similar genetic determinants governing basal expression and hormonal responsiveness in pituitary cells.