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DOI	10.1073/pnas.2114258118
	Calcineurin regulates the stability and activity of estrogen receptor α
	Masaki T.; Habara M.; Sato Y.; Goshima T.; Maeda K.; Hanaki S.; Shimada M.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:44
英文摘要	Estrogen receptor α (ER-α) mediates estrogen-dependent cancer progression and is expressed in most breast cancer cells. However, the molecular mechanisms underlying the regulation of the cellular abundance and activity of ER-α remain unclear. We here show that the protein phosphatase calcineurin regulates both ER-α stability and activity in human breast cancer cells. Calcineurin depletion or inhibition down-regulated the abundance of ER-α by promoting its polyubiquitination and degradation. Calcineurin inhibition also promoted the binding of ER-α to the E3 ubiquitin ligase E6AP, and calcineurin mediated the dephosphorylation of ER-α at Ser294 in vitro. Moreover, the ER-α (S294A) mutant was more stable and activated the expression of ER-α target genes to a greater extent compared with the wild-type protein, whereas the extents of its interaction with E6AP and polyubiquitination were attenuated. These results suggest that the phosphorylation of ER-α at Ser294 promotes its binding to E6AP and consequent degradation. Calcineurin was also found to be required for the phosphorylation of ER-α at Ser118 by mechanistic target of rapamycin complex 1 and the consequent activation of ER-α in response to β-estradiol treatment. Our study thus indicates that calcineurin controls both the stability and activity of ER-α by regulating its phosphorylation at Ser294 and Ser118. Finally, the expression of the calcineurin A-α gene (PPP3CA) was associated with poor prognosis in ER-α-positive breast cancer patients treated with tamoxifen or other endocrine therapeutic agents. Calcineurin is thus a promising target for the development of therapies for ER-α-positive breast cancer. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Breast cancer; Calcineurin; Estrogen receptorα; Ubiquitination
语种	英语
scopus关键词	calcineurin; estradiol; estrogen receptor alpha; mammalian target of rapamycin complex 1; mutant protein; serine; tamoxifen; ubiquitin protein ligase E3; calcineurin; ESR1 protein, human; estradiol; estrogen; estrogen receptor; estrogen receptor alpha; PPP3CA protein, human; proteasome; UBE3A protein, human; ubiquitin; ubiquitin protein ligase; Article; cancer hormone therapy; cancer inhibition; cancer prognosis; cohort analysis; controlled study; disease association; embryo; enzyme inhibition; estrogen receptor positive breast cancer; gene expression; human; human cell; in vitro study; MCF-7 cell line; oncogene; PPP3CA gene; protein degradation; protein dephosphorylation; protein depletion; protein expression; protein function; protein phosphorylation; protein protein interaction; protein stability; receptor binding; receptor down regulation; ubiquitination; breast tumor; drug effect; female; gene expression regulation; genetics; metabolism; physiology; protein processing; tumor cell line; Breast Neoplasms; Calcineurin; Cell Line, Tumor; Estradiol; Estrogen Receptor alpha; Estrogens; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Receptors, Estrogen; Ubiquitin; Ubiquitin-Protein Ligases; Ubiquitination
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/251001
作者单位	Department of Biochemistry, Joint Faculty of Veterinary Science, Yamaguchi University, Yamaguchi, 753-8511, Japan; Department of Cell Biology, Graduate School of Medical Sciences, Nagoya City University, Nagoya, 467-8601, Japan
推荐引用方式 GB/T 7714	Masaki T.,Habara M.,Sato Y.,et al. Calcineurin regulates the stability and activity of estrogen receptor α[J],2021,118(44).
APA	Masaki T..,Habara M..,Sato Y..,Goshima T..,Maeda K..,...&Shimada M..(2021).Calcineurin regulates the stability and activity of estrogen receptor α.Proceedings of the National Academy of Sciences of the United States of America,118(44).
MLA	Masaki T.,et al."Calcineurin regulates the stability and activity of estrogen receptor α".Proceedings of the National Academy of Sciences of the United States of America 118.44(2021).