| 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
|
| リソース情報 |
| 遺伝子材料 |
CS-RfA-ETBsd (RDB07917)
pCMV-VSV-G-RSV-Rev (RDB04393)
pCAG-HIVgp (RDB04394) |
