論文 - 詳細
| RRC ID | 68978 |
|---|---|
| 著者 | Masaki T, Habara M, Sato Y, Goshima T, Maeda K, Hanaki S, Shimada M. |
| タイトル | Calcineurin regulates the stability and activity of estrogen receptor α. |
| ジャーナル | Proc Natl Acad Sci U S A |
| Abstract |
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. |
| 巻・号 | 118(44) |
| 公開日 | 2021-11-2 |
| DOI | 10.1073/pnas.2114258118 |
| PII | 2114258118 |
| PMID | 34711683 |
| PMC | PMC8612228 |
| MeSH | Breast Neoplasms / metabolism* Calcineurin / metabolism* Calcineurin / physiology Cell Line, Tumor Estradiol / pharmacology Estrogen Receptor alpha / drug effects Estrogen Receptor alpha / metabolism* Estrogens / metabolism Female Gene Expression / genetics Gene Expression Regulation, Neoplastic / genetics Humans Proteasome Endopeptidase Complex / metabolism Protein Processing, Post-Translational / drug effects Receptors, Estrogen / drug effects Receptors, Estrogen / metabolism Ubiquitin / metabolism Ubiquitin-Protein Ligases / metabolism Ubiquitination / drug effects |
| IF | 9.412 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 1 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 遺伝子材料 | CS-RfA-ETBsd (RDB07917) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394) |