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RSK2 Maintains Adult Estrogen Homeostasis by Inhibiting ERK1/2-Mediated Degradation of Estrogen Receptor Alpha

In response to estrogens, estrogen receptor alpha (ERα), a critical regulator of homeostasis, is degraded through the 26S proteasome. However, despite the continued presence of estrogen before menopause, ERα protein levels are maintained. We discovered that ERK1/2-RSK2 activity oscillates during the...

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Autores principales: Ludwik, Katarzyna A., Sandusky, Zachary M., Stauffer, Kimberly M., Li, Yu, Boyd, Kelli L., O’Doherty, George A., Stricker, Thomas P., Lannigan, Deborah A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465694/
https://www.ncbi.nlm.nih.gov/pubmed/32697984
http://dx.doi.org/10.1016/j.celrep.2020.107931
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author Ludwik, Katarzyna A.
Sandusky, Zachary M.
Stauffer, Kimberly M.
Li, Yu
Boyd, Kelli L.
O’Doherty, George A.
Stricker, Thomas P.
Lannigan, Deborah A.
author_facet Ludwik, Katarzyna A.
Sandusky, Zachary M.
Stauffer, Kimberly M.
Li, Yu
Boyd, Kelli L.
O’Doherty, George A.
Stricker, Thomas P.
Lannigan, Deborah A.
author_sort Ludwik, Katarzyna A.
collection PubMed
description In response to estrogens, estrogen receptor alpha (ERα), a critical regulator of homeostasis, is degraded through the 26S proteasome. However, despite the continued presence of estrogen before menopause, ERα protein levels are maintained. We discovered that ERK1/2-RSK2 activity oscillates during the estrous cycle. In response to high estrogen levels, ERK1/2 is activated and phosphorylates ERα to drive ERα degradation and estrogen-responsive gene expression. Reduction of estrogen levels results in ERK1/2 deactivation. RSK2 maintains redox homeostasis, which prevents sustained ERK1/2 activation. In juveniles, ERK1/2-RSK2 activity is not required. Mammary gland regeneration demonstrates that ERK1/2-RSK2 regulation of ERα is intrinsic to the epithelium. Reduced RSK2 and enrichment in an estrogen-regulated gene signature occur in individuals taking oral contraceptives. RSK2 loss enhances DNA damage, which may account for the elevated breast cancer risk with the use of exogenous estrogens. These findings implicate RSK2 as a critical component for the preservation of estrogen homeostasis.
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spelling pubmed-74656942020-09-02 RSK2 Maintains Adult Estrogen Homeostasis by Inhibiting ERK1/2-Mediated Degradation of Estrogen Receptor Alpha Ludwik, Katarzyna A. Sandusky, Zachary M. Stauffer, Kimberly M. Li, Yu Boyd, Kelli L. O’Doherty, George A. Stricker, Thomas P. Lannigan, Deborah A. Cell Rep Article In response to estrogens, estrogen receptor alpha (ERα), a critical regulator of homeostasis, is degraded through the 26S proteasome. However, despite the continued presence of estrogen before menopause, ERα protein levels are maintained. We discovered that ERK1/2-RSK2 activity oscillates during the estrous cycle. In response to high estrogen levels, ERK1/2 is activated and phosphorylates ERα to drive ERα degradation and estrogen-responsive gene expression. Reduction of estrogen levels results in ERK1/2 deactivation. RSK2 maintains redox homeostasis, which prevents sustained ERK1/2 activation. In juveniles, ERK1/2-RSK2 activity is not required. Mammary gland regeneration demonstrates that ERK1/2-RSK2 regulation of ERα is intrinsic to the epithelium. Reduced RSK2 and enrichment in an estrogen-regulated gene signature occur in individuals taking oral contraceptives. RSK2 loss enhances DNA damage, which may account for the elevated breast cancer risk with the use of exogenous estrogens. These findings implicate RSK2 as a critical component for the preservation of estrogen homeostasis. 2020-07-21 /pmc/articles/PMC7465694/ /pubmed/32697984 http://dx.doi.org/10.1016/j.celrep.2020.107931 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Ludwik, Katarzyna A.
Sandusky, Zachary M.
Stauffer, Kimberly M.
Li, Yu
Boyd, Kelli L.
O’Doherty, George A.
Stricker, Thomas P.
Lannigan, Deborah A.
RSK2 Maintains Adult Estrogen Homeostasis by Inhibiting ERK1/2-Mediated Degradation of Estrogen Receptor Alpha
title RSK2 Maintains Adult Estrogen Homeostasis by Inhibiting ERK1/2-Mediated Degradation of Estrogen Receptor Alpha
title_full RSK2 Maintains Adult Estrogen Homeostasis by Inhibiting ERK1/2-Mediated Degradation of Estrogen Receptor Alpha
title_fullStr RSK2 Maintains Adult Estrogen Homeostasis by Inhibiting ERK1/2-Mediated Degradation of Estrogen Receptor Alpha
title_full_unstemmed RSK2 Maintains Adult Estrogen Homeostasis by Inhibiting ERK1/2-Mediated Degradation of Estrogen Receptor Alpha
title_short RSK2 Maintains Adult Estrogen Homeostasis by Inhibiting ERK1/2-Mediated Degradation of Estrogen Receptor Alpha
title_sort rsk2 maintains adult estrogen homeostasis by inhibiting erk1/2-mediated degradation of estrogen receptor alpha
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465694/
https://www.ncbi.nlm.nih.gov/pubmed/32697984
http://dx.doi.org/10.1016/j.celrep.2020.107931
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