Publication Date:
2022-05-26
Description:
Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Journal of Steroid Biochemistry and Molecular Biology 127 (2011): 176–188, doi:10.1016/j.jsbmb.2011.03.022.
Description:
Classically, the estrogen signaling system has two core components: cytochrome P450
aromatase (CYP19), the enzyme complex that catalyzes the rate limiting step in estrogen
biosynthesis; and estrogen receptors (ERs), ligand activated transcription factors that interact
with the regulatory region of target genes to mediate the biological effects of estrogen. While the
importance of estrogens for regulation of reproduction, development and physiology has been
well-documented in gnathostome vertebrates, the evolutionary origins of estrogen as a hormone
are still unclear. As invertebrates within the phylum Chordata, cephalochordates (e.g. the
amphioxus of the genus Branchiostoma) are among the closest invertebrate relatives of the
vertebrates and can provide critical insight into the evolution of vertebrate-specific molecules
and pathways. To address this question, this paper briefly reviews relevant earlier studies that
help to illuminate the history of the aromatase and ER genes, with a particular emphasis on
insights from amphioxus and other invertebrates. We then present new analyses of amphioxus
aromatase and ER sequence and function, including an in silico model of the amphioxus
aromatase protein, and CYP19 gene analysis. CYP19 shares a conserved gene structure with
vertebrates (9 coding exons) and moderate sequence conservation (40% amino acid identity with
human CYP19). Modeling of the amphioxus aromatase substrate binding site and simulated
docking of androstenedione in comparison to the human aromatase shows that the substrate
binding site is conserved and predicts that androstenedione could be a substrate for amphioxus
CYP19. The amphioxus ER is structurally similar to vertebrate ERs, but differs in sequence and
key residues of the ligand binding domain. Consistent with results from other laboratories,
amphioxus ER did not bind radiolabeled estradiol, nor did it modulate gene expression on an estrogen-responsive element (ERE) in the presence 59 of estradiol, 4-hydroxytamoxifen,
diethylstilbestrol, bisphenol A or genistein. Interestingly, it has been shown that a related gene,
the amphioxus “steroid receptor” (SR), can be activated by estrogens and that amphioxus ER can
repress this activation. CYP19, ER and SR are all primarily expressed in gonadal tissue,
suggesting an ancient paracrine/autocrinesignaling role, but it is not yet known how their
expression is regulated and, if estrogen is actually synthesized in amphioxus, whether it has a
role in mediating any biological effects . Functional studies are clearly needed to link emerging
bioinformatics and in vitro molecular biology results with organismal physiology to develop an
understanding of the evolution of estrogen signaling.
Description:
Supported by grants from the NIEHS P42 ES07381 (GVC, SV) and EPA (STAR-RD831301)
(GVC), a Ruth L Kirschstein National Research Service Award (AT, F32 ES013092-01), an NIH
traineeship (SS, SG), a NATO Fellowship (AN) and the Boston University Undergraduate
Research Program (LC).
Keywords:
Estrogen
;
Aromatase
;
Estrogen receptors
;
Evolution
;
Amphioxus
Repository Name:
Woods Hole Open Access Server
Type:
Preprint
Format:
application/pdf
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