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J Biol Chem. 2013 Sep 6;288(36):26265-74. doi: 10.1074/jbc.M113.476556. Epub 2013 Jul 23.

Progesterone receptor A stability is mediated by glycogen synthase kinase-3β in the Brca1-deficient mammary gland.

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  • 1Department of Biological Chemistry, University of California Irvine, Irvine, California 92697, USA.

Abstract

Germ line mutations of the BRCA1 gene increase the risk of breast and ovarian cancer, but the basis of this tissue-specific tumor predisposition is not fully understood. Previously, we reported that the progesterone receptors are stabilized in Brca1-deficient mammary epithelial cells, and treating with anti-progesterone delays mammary tumorigenesis in Brca1/p53 conditional knock-out mice, suggesting that the progesterone has a critical role in breast carcinogenesis. To further explore how the stability of progesterone receptor is modulated, here, we have found that glycogen synthase kinase (GSK)-3β phosphorylation of progesterone receptor-A (PR-A) facilitates its ubiquitination. GSK-3β-mediated phosphorylation of serine 390 in PR-A regulates its subsequent ubiquitination and protein stability. Expression of PR-A(S390A) mutant in the human breast epithelial cells, MCF-10A, results in enhanced proliferation and formation of aberrant acini structure in the three-dimensional culture. Consistently, reduction of phosphorylation of serine 390 of PR-A and GSK-3β activity is observed in the Brca1-deficient mammary gland. Taken together, these results provide important aspects of tissue specificity of BRCA1-mediated suppression of breast carcinogenesis.

KEYWORDS:

BRCA1; Bard1; Breast Cancer; GSK-3; Mammary Gland; PR-A; Phosphorylation; Protein Degradation; Ubiquitination

PMID:
23880761
[PubMed - indexed for MEDLINE]
PMCID:
PMC3764830
Free PMC Article
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