RRC ID 68978
Author Masaki T, Habara M, Sato Y, Goshima T, Maeda K, Hanaki S, Shimada M.
Title Calcineurin regulates the stability and activity of estrogen receptor α.
Journal 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.
Volume 118(44)
Published 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
DNA material CS-RfA-ETBsd (RDB07917) pCMV-VSV-G-RSV-Rev (RDB04393) pCAG-HIVgp (RDB04394)