Extracellular signal-regulated kinase 7, a regulator of hormone-dependent estrogen receptor destruction |
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Authors: | Henrich Lorin M Smith Jeffrey A Kitt Danielle Errington Timothy M Nguyen Binh Traish Abdulmaged M Lannigan Deborah A |
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Affiliation: | Department of Microbiology and Center for Cell Signaling, University of Virginia, Charlottesville, Virginia 22908, USA. |
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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. |
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