Abstract
The nuclear hormone receptor, estrogen receptor α (ERα), and mitogen-activated protein kinases (MAPKs) play key roles in hormone-dependent cancers, and yet their interplay and the integration of their signaling inputs remain poorly understood. In these studies, we document that estrogen-occupied ERα activates and interacts with extracellular signal-regulated kinase 2 (ERK2), a downstream effector in the MAPK pathway, resulting in ERK2 and ERα colocalization at chromatin binding sites across the genome of breast cancer cells. This genomic colocalization, predominantly at conserved distal enhancer sites, requires the activation of both ERα and ERK2 and enables ERK2 modulation of estrogen-dependent gene expression and proliferation programs. The ERK2 substrate CREB1 was also activated and recruited to ERK2-bound chromatin following estrogen treatment and found to cooperate with ERα/ERK2 in regulating gene transcription and cell cycle progression. Our study reveals a novel paradigm with convergence of ERK2 and ERα at the chromatin level that positions this kinase to support nuclear receptor activities in crucial and direct ways, a mode of collaboration likely to underlie MAPK regulation of gene expression by other nuclear receptors as well.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Binding Sites / genetics
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chromatin / genetics
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Chromatin / metabolism
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Cyclic AMP Response Element-Binding Protein / metabolism
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Estradiol / metabolism
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Estradiol / pharmacology
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Estrogen Receptor alpha / genetics*
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Estrogen Receptor alpha / metabolism*
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Female
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Gene Expression Regulation, Neoplastic
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Gene Knockdown Techniques
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Genome, Human
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Humans
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MAP Kinase Signaling System
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / genetics*
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Models, Biological
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Neoplasms, Hormone-Dependent / genetics
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Neoplasms, Hormone-Dependent / metabolism
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Neoplasms, Hormone-Dependent / pathology
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Oligonucleotide Array Sequence Analysis
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RNA, Small Interfering / genetics
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism
Substances
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CREB1 protein, human
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Chromatin
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Cyclic AMP Response Element-Binding Protein
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ESR1 protein, human
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Estrogen Receptor alpha
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RNA, Small Interfering
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Receptors, Cytoplasmic and Nuclear
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Estradiol
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3