Recent insights into the origins of adrenal and sex steroid receptors

Abstract

The recent cloning by Thornton (2001) of estrogen, progesterone and corticoid receptors from lamprey provides important insights into the early evolution of adrenal and sex steroid receptors and an opportunity to elucidate the ancient steroids that regulated gene transcription. Inclusion of lamprey sequences in a steroid receptor phylogeny indicates that the estrogen receptor is the most ancient of these receptors, followed by the progesterone receptor and the corticoid receptor. Thornton proposed that estradiol was the earliest of the steroids to activate a steroid receptor. An alternative hypothesis is that a steroid in the ∆ 5 pathway activated the ancestral estrogen receptor.

Evolution of adrenal and sex steroid action in vertebrates: a ligand‐based mechanism for complexity

“…An ER, PR and corticoid receptor (CR) have been cloned from lamprey, a jawless fish [18,19]. It appears that the ER is the most ancient of the adrenal and sex steroid receptors [8,18].…”

Insights from the structure of estrogen receptor into the evolution of estrogens: Implications for endocrine disruption

“…In an alternative model, 5-androsten-3 ,17 -diol [ 5 -androstenediol], which is upstream of E2, has been proposed as a ligand for the ancestral ER [22][23] [ Figure 3]. Here, we provide support for this latter hypothesis, using data from crystal structures of human ER with E2 and other steroids and 3D models of human ER with 5 steroids.…”

“…Duplication of this ER followed by sequence divergence led to the ancestral 3-keto-steroid receptor, which through further duplications and divergence led to the AR, GR, MR and PR [1,[6][7]. A problem with having the ER as the ancestral receptor is that estradiol [E2], the physiological ligand for vertebrate ERs, is at the end of the pathway for the synthesis of steroids from cholesterol [7,22] [ Figure 2]. …”

“…However, steroids that lack an aromatic A ring and contain a 3 -hydroxyl group, such as 5 -androstenediol and 5 -androstane-3 ,17 -diol [3 -Adiol] also have high affinity for the mammalian ER [30] and could have served as ligands for the ancestral ER [22][23]. Indeed, 3 -Adiol is an active estrogen in the prostate [35], as well as in the brain, under conditions in which E2 is not present [36].…”

“…Thus, either steroid could have been an active estrogen before the evolution of CYP19. Moreover, 5 -androstenediol could have been an active estrogen before the evolution of 3 / 5-4 -HSD [22][23].…”