Abstract
Estrogen receptor alpha (ER alpha) degradation is regulated by ubiquitination, but the signaling pathways that modulate ER alpha turnover are unknown. We found that extracellular signal-regulated kinase 7 (ERK7) preferentially enhances the destruction of ER alpha but not the related androgen receptor. Loss of ERK7 was correlated with breast cancer progression, and all ER alpha-positive breast tumors had decreased ERK7 expression compared to that found in normal breast tissue. In human breast cells, a dominant-negative ERK7 mutant decreased the rate of endogenous ER alpha degradation >4-fold in the presence of hormone and potentiated estrogen responsiveness. ERK7 targets the ER alpha ligand-binding domain for destruction by enhancing its ubiquitination. Thus, ERK7 is a novel regulator of estrogen responsiveness through its control of ER alpha turnover.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding Sites
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Breast / cytology
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cells, Cultured
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Cricetinae
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Cysteine Proteinase Inhibitors / pharmacology
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Estrogen Receptor alpha
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Extracellular Signal-Regulated MAP Kinases*
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Female
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Hormones / metabolism*
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Hormones / pharmacology
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Humans
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Kidney / cytology
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Leupeptins / pharmacology
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism*
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Mutation
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Peptide Hydrolases / drug effects
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Peptide Hydrolases / metabolism
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Phosphorylation
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Proteasome Endopeptidase Complex*
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Receptors, Estrogen / drug effects
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Receptors, Estrogen / genetics
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Receptors, Estrogen / metabolism*
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Reference Values
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Signal Transduction
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Ubiquitin / metabolism
Substances
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Cysteine Proteinase Inhibitors
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Estrogen Receptor alpha
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Hormones
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Leupeptins
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Receptors, Estrogen
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Ubiquitin
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Extracellular Signal-Regulated MAP Kinases
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Mapk15 protein, rat
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Mitogen-Activated Protein Kinases
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Peptide Hydrolases
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Proteasome Endopeptidase Complex
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ATP dependent 26S protease
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde