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unknown
Evolutionary origins of the estrogen signaling system : insights from amphioxus
Authors
A. Novillo
A.M. Tarrant
+119 more
Abascal
Amarneh
Baker
Berman
Brenke
Bridgham
Bulun
C. Hoover
Callard
Callard
Callard
Canesi
Castro
Chen
Chen
Chen
Chiang
Chow
Conley
Corbin
D. Kozakov
Elliston
Engel
Eswar
Felsenstein
Fitzpatrick
G.-Y. Chuang
G.V. Callard
Gates
Gelinas
Ghosh
Ghosh
Glass
Graham-Lorence
Green
Greytak
Greytak
Greytak
Hajduk
Hall
Hawkins
Heldring
Herynk
Hirata
Holland
Honda
Jensen
K.A. Cotter
Kamat
Kao
Karchner
Katsu
Kazeto
Keay
Keay
Kel
Kishida
Kishida
Kos
Kuiper
Kuiper
Kumar
Kumar
L. Ciaccia
Landon
Landon
Landon
Levin
Losel
Mahendroo
Markov
Marti-Renom
Matsumoto
Mattos
McDonald
Mizuta
Mizuta
Morris
Nelson
Ngan
P. Yacci
Pang
Paris
Pedram
Pedram
Poola
Poola
Poola
Powell
Pratt
Ramachandran
Reitzel
S. Sawyer
S. Vajda
S.R. Greytak
Safe
Santen
Schubert
Sheu
Shimozawa
Shozu
Simpson
Stamatakis
Tchoudakova
Tchoudakova
Thomas
Thomas
Thornton
Thornton
Tong
Tong
Tora
Vanacker
Wang
Wendler
Wittmann
Zeitoun
Zhao
Zwart
Publication date
6 April 2011
Publisher
'Elsevier BV'
Doi
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on
PubMed
Abstract
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.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.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)
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