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Progesterone Receptor A Stability Is Mediated by Glycogen Synthase Kinase-3β in the Brca1-deficient Mammary Gland
- Source :
- Journal of Biological Chemistry. 288:26265-26274
- Publication Year :
- 2013
- Publisher :
- Elsevier BV, 2013.
-
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-AS390A 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. Background: Stabilization of progesterone receptors contributes to mammary tumorigenesis in Brca1-deficient mice. Results: Deficiency in phosphorylation on serine 390 of progesterone receptor A by GSK-3β enhances the receptor stability. Conclusion: Stabilization of progesterone receptor A is mediated by GSK-3β kinase in the Brca1-deficient mammary gland. Significance: This finding provides a novel insight of how tumor suppression of Brca1 is mediated by PR-A.
- Subjects :
- Progesterone receptor A
endocrine system diseases
Mammary gland
Mutation, Missense
Breast Neoplasms
Mammary Neoplasms, Animal
Protein degradation
Biology
Biochemistry
Glycogen Synthase Kinase 3
Mice
Mammary Glands, Animal
GSK-3
Cell Line, Tumor
Progesterone receptor
medicine
Animals
Humans
Phosphorylation
Mammary Glands, Human
skin and connective tissue diseases
Receptor
Molecular Biology
Mice, Knockout
Glycogen Synthase Kinase 3 beta
BRCA1 Protein
Protein Stability
Kinase
Molecular Bases of Disease
Cell Biology
medicine.anatomical_structure
Cancer research
Female
Receptors, Progesterone
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 288
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....86c29cb35b5de962741ab4991b94e4de