Relationship of estrogen receptors and protein synthesis to the mitogenic effect of estrogens.

1,3,5(10)-Estratriene-3,16 alpha-diol (16 alpha-E2) is an estrogen which is ineffective in stimulating DNA synthesis in the prepuberal rat uterus when administered to rats in a single injection in doses up to at least 5 micrograms. However, it acquires the same high mitogenic potency as 1,3,5(10)-estratriene-3,17 beta-diol (17 beta-E2) if a 5-micrograms dose is administered over a 12-h period via sequential injections of 1 microgram each at 3-h intervals. In an attempt to explain this phenomenon we have found that the ability of an estrogen to maintain a stimulated rate of protein synthesis for 12 h correlates directly with its ability to stimulate DNA synthesis. A single injection of 16 alpha-E2 stimulates protein synthesis at 4 h to a degree comparable to 17 beta-E2. By 12 h when the effect of 17 beta-E2 is maximal, the effect of one injection of 16 alpha-E2 has diminished to control levels. However, if 16 alpha-E2 is administered via sequential injections at 3-h intervals, protein synthesis at 12 h is stimulated to the same extent achieved by a single injection of 17 beta-E2. We also have examined the fate of estrogen receptors in relationship to these changes in protein and DNA synthesis. The effects of a single injection of 16 alpha-E2 differ in four respects from those of 17 beta-E2: 1) the retention of receptors in the nuclear form is shorter; 2) replenishment of receptors to the cytosolic form is more rapid and greater than 80% complete within 3 h; 3) fewer receptors are processed, i.e. the loss of receptors detectable by exchange assay is smaller; and 4) the overshoot in receptor replenishment 24 h after an injection is smaller. Overall, the stimulation of DNA synthesis is positively related to the rate of protein synthesis 12 h after an injection of estrogen, the retention of receptors in the nuclear form, and the amount of receptor processing.