Regulation by Progestins, Corticosteroids and RU486 of Activation of Elephant Shark and Human Progesterone Receptors: An Evolutionary Perspective

Abstract

We investigated progestin and corticosteroid activation of the progesterone receptor (PR) from elephant shark (Callorhinchus milii), a cartilaginous fish belonging to the oldest group of jawed vertebrates. Comparison with human PR experiments provides insights into the evolution of steroid activation of human PR. At 1 nM steroid, elephant shark PR is activated by progesterone, 17-hydroxy-progesterone, 20β-hydroxy-progesterone, 11-deoxycorticosterone (21-hydroxyprogesterone) and 11-deoxycortisol. At 1 nM steroid, human PR is activated only by progesterone and11-deoxycorticosterone indicating increased specificity for progestins and corticosteroids during the evolution of human PR. RU486, an important clinical antagonist of human PR, did not inhibit progesterone activation of elephant shark PR. Cys-528 in elephant shark PR corresponds to Gly-722 in human PR, which is essential for RU486 inhibition of human PR. Confirming the importance of this site on elephant shark PR, RU486 inhibited progesterone activation of the Cys528Gly mutant PR. There also was a decline in activation of elephant shark Cys528Gly PR by 11-deoxycortisol, 17-hydroxy-progesterone and 20β-hydroxy-progesterone and an increase in activation of human Gly722Cys PR by 11-deoxycortisol and decreased activation by corticosterone. One or more of these changes may have selected for the mutation corresponding to human glycine-722 PR that first evolved in platypus PR, a basal mammal.

Divergent evolution of progesterone and mineralocorticoid receptors in terrestrial vertebrates and fish influences endocrine disruption

“…Ray-finned fish PR respond weakly to progesterone [52][53][54], while human PR and elephant shark PR are activated by progesterone [55]. Spironolactone, which has structural similarities to progesterone activates ray-finned fish PR and elephant shark PR [55], while spironolactone inhibits transcriptional activation of human PR [31]. Progesterone and spironolactone activate elephant shark MR and ray-finned fish MR and inhibit transcriptional activation of human MR.…”

“…Similar to human PR, elephant shark PR has a low EC50 (0.18 nM) for progesterone (Table 1). However, compared to human PR, the response to hydroxylated progesterone analogs is very different in elephant shark PR, which has low EC50s for 17a-OH-Prog (EC50=0.36 nM) and 17α,20β-P (EC50=2.6 nM) (Figure 2) (Table 1) [55], two steroids that have little activity for human PR (Table 1). Like elephant shark PR, fish PR has a strong response to 17,20b-P, which is important in fish reproductive physiology, including acting as a maturation inducing hormone of teleost fish [52,[56][57][58][59][60].…”

“…Structures of steroids that activate the progesterone receptor and mineralocorticoid receptors in elephant shark, ray-finned fish and humans.The physiological progestins for the PR in zebrafish and other ray-finned fish are 17,20bdihydroxy-progesterone and 17,20β,21-trihydroxy-pregn-4-en-3-one, which also activate elephant shark PR (Table2)[52]. Ray-finned fish PR respond weakly to progesterone[52][53][54], while human PR and elephant shark PR are activated by progesterone[55]. Spironolactone, which has structural similarities to progesterone activates ray-finned fish PR and elephant shark PR[55], while spironolactone inhibits transcriptional activation of human PR[31].…”