The establishment and maintenance of pregnancy requires the coordinate hormonal regulation of corpus luteum function. Extensive investigation from out laboratory has established a key role for estradiol and PRL in such regulation. Our research has led us to isolate a corpus luteum gene, 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD), whose expression is markedly inhibited by PRL. We have also discovered a novel protein, named PRAP, that associates with the intracellular domain of the short form of the PRL-receptor and whose expression is tightly regulated by estradiol. Most interestingly, the PRL inhibition of the 20alpha-HSD gene expression occurs through the short form of the PRL-receptor. In the first part of this investigation, we will determine the mechanism of PRL-signaling through the PRL-receptor short form using luteal derived cell lines generated in our laboratory. We will also define the role of PRAP in PRL signaling through this receptor type. Because stimulation of luteal 20alpha-HSD expression by LH/PGF/2a plays a key role in lowering progesterone production and allowing for parturition, we will investigate the molecular mechanism by which these hormones up regulate 20alpha-HSD gene expression. Our recent investigations have revealed that the synergism between PRL and estradiol action in luteal cells involves PRL stimulation of both estradiol receptor (alpha and beta) mRNAs and estradiol induction of PRAP expression. Estradiol and PRL also act together on elongation factor 2, a peptide involved in protein translation, to respective enhance its levels and state of phosphorylation. We will therefore investigate in the last specific aim the molecular mechanism by which estradiol and PRL attest in the luteal cell, the expression and state of phosphorylation of proteins involved in their respective signaling and in protein translation.
Showing the most recent 10 out of 78 publications
