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

Cell Reports
Katarzyna A LudwikDeborah Lannigan

Abstract

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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Citations

Oct 18, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Claes OhlssonMarie K Lagerquist
Nov 26, 2020·Molecular & Cellular Oncology·Katarzyna A Ludwik, Deborah A Lannigan
Jan 26, 2021·STAR Protocols·Katarzyna A LudwikDeborah A Lannigan

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Datasets Mentioned

BETA
GSE113323

Methods Mentioned

BETA
transgenic
fluorescence-activated cell sorting
FACS
electrophoretic
hormone-replacement therapy
PCR
Flow
Assay

Software Mentioned

STAR
GSVA
Gencode
DESeq2
SVA
GSEA

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