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ERK1/2-RSK2 signaling is a developmental switch required for estrogen homeostasis

ABSTRACT: Transcriptomic analysis of the mature ER+ population in the mammary gland revealed enrichment for estrogen-responsive genes in the RSK2-KO compared to the wild type.

ORGANISM(S): Mus musculus

PROVIDER: GSE113323 | GEO | 2020/09/08

REPOSITORIES: GEO

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ERK1/2-RSK2 signaling is a developmental switch required for estrogen homeostasis

Project description:ERK1/2-RSK2 signaling is a developmental switch required for estrogen homeostasis

| PRJNA450817 | ENA

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

Project description:In response to estrogens, estrogen receptor alpha (ER?), a critical regulator of homeostasis, is degraded through the 26S proteasome. However, despite the continued presence of estrogen before menopause, ER? 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 ER? to drive ER? 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 ER? 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.

| S-EPMC7465694 | biostudies-literature

RSK2-regulated gene signature associates with ER+ breast cancer

Project description:We used CRISPR RSK2 knock-out MCF-7 cells to identify RSK2-regulated genes.

2020-06-01 | GSE99707 | GEO

RSK2 is a modulator of craniofacial development

Project description:The RSK2 gene is responsible for Coffin-Lowry syndrome, an X-linked monogenic disease associating severe learning deficit andassociated to typical facial and digital abnormalities and skeletal changes. Craniofacial and dental anomalies encountered in this rare disease have been poorly characterized. In this study we explore, through X-Ray microtomographic analysis, the variable craniofacial dysmorphism and dental anomalies present in Rsk2 knockout mice, an animal model of Coffin-Lowry syndrome, as well as in triple Rsk1,2,3 knockout mutants. We report in these mutants the occurrence of a surpernumerary tooth mesial to the first molar. This highly penetrant phenotype is considered as a remnant of evolutionary lost teeth. This possibly leads to the significant reduction of the maxillary diastema. Abnormalities of molar shape were almost restricted to the mesial part of both upper and lower first molars (M1). We also report an expression analysis of the four Rsk genes (Rsk1, 2, 3 and 4) at various stages of odontogenesis in wild-type (WT) mice. Rsk2 was mainly expressed in the mesenchymal, neural crest derived compartment, correlating with proliferative areas of the developing teeth and consistent with a biological function of RSK2 in cell cycle control and cell growth, which when invalidated could be responsible for the dental phenotype. In an attempt to unravel the molecular pathways involved in the genesis of these dental defects, we performed a comparative transcriptomic (DNA microarray) analysis of mandibular wild-type versus Rsk2-/Y molars, and further demonstrated a misregulation of selected genes, using a Rsk2 shRNA knock-down strategy in molar tooth germs cultured in vitro.

2014-01-13 | E-GEOD-51034 | biostudies-arrayexpress

HDXMS of ERK2-RSK2 and ERK2-RSK2-ORF45 complexes

Project description:Hydrogen deuterium exchange mass spectrometry data of the ERK2-RSK2 and ERK2-RSK2-ORF45 complexes. The noncatalytic viral protein ORF45 reconfigures ERK-RSK signaling in cells. This dataset identifies the ORF45-RSK2 interface.

2021-12-22 | MSV000088607 | MassIVE

Expression profiles of the hippocampus of Rsk2-KO mice

Project description:Coffin–Lowry Syndrome (CLS) is a syndromic form of mental retardation caused by loss of function mutations in the X-linked RPS6KA3 gene, which encodes Rsk2, a serine/threonine kinase involved in spatial memory. We analyzed hippocampal gene expression profiles in Rsk2-KO mice to identify changes in molecular pathways. Total RNA was extracted from hippocampi from 6 KO and 6 WT (littermates) 2-month-old male mice. For each genotype, equivalent amounts of RNA from 2 mice were pooled and processed for hybridization to the genome wide oligonucleotide microarray (Murine 430A 2.0 Affymetrix, 22.000 probe sets). Thus, 3 independent pooled samples were hybridized for each genotype. We compared hippocampal gene expression profiles from rsk2-KO and normal littermate mice to identify changes in molecular pathways

2010-12-22 | E-GEOD-22137 | biostudies-arrayexpress

The effects on oncogenic pathway, signaling, by RSK2 N-terminal kinase inhibitor (BI-D1870) in Mantle cell lymphoma-derived cell lines.

Project description:RSK2 is a serine/threonine kinase downstream signaling mediator in the RAS/ERK signaling pathway and may be a therapeutic target in mantle cell lymphoma (MCL). RSK2-Ser227 in the N-terminal kinase domain (NTKD) of RSK2 was found to be ubiquitously active in five MCL-derived cell lines and in tumor tissues derived from five MCL patients. BI-D1870, an inhibitor specific to RSK2-NTKD, caused RSK2-Ser227 dephosphorylation, and thereby, induced dose-dependent growth inhibition via G2/M cell cycle blockade and apoptosis. Comparative gene expression profiling of the MCL-derived cell lines showed that inhibition of RSK2-Ser227 by BI-D1870 caused downregulation of oncogenes, such c-MYC and MYB; anti-apoptosis genes, such as BCL2 and BCL2L1; genes for B cell development, including IKZF1, IKZF3 and PAX5; and genes constituting the B cell receptor signaling pathway, such as CD19, CD79B and BLNK. These findings show that targeting of RSK2-Ser227 enables concomitant blockade of pathways that are critically important in B cell tumorigenesis.

2020-03-25 | GSE147484 | GEO

RSK2 is a modulator of craniofacial development

2014-01-13 | GSE51034 | GEO

Rsk2 controls synovial fibroblast hyperplasia and the course of arthritis.

Project description:To understand differences in the pathogenesis of synovial hyperplasia during TNF-induced arthritis, we compared the global gene expression of hTNFtg and hTNFtg;Rsk2-/y primary synovial fibroblasts.

2014-12-04 | GSE52992 | GEO

Expression profiles of the hippocampus of Rsk2-KO mice

2010-12-22 | GSE22137 | GEO