Interaction of the double-strand break repair kinase DNA-PK and estrogen receptor-alpha

Estrogens are suggested to play a role in the development and progression of proliferative diseases such as breast cancer. Like other steroid hormone receptors, the estrogen receptor-alpha (ERalpha) is a substrate of protein kinases, and phosphorylation has profound effects on its function and activ...

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Bibliographic Details
Published in:Molecular biology of the cell 2010-05, Vol.21 (9), p.1620-1628
Main Authors: Medunjanin, Senad, Weinert, Sönke, Schmeisser, Alexander, Mayer, Doris, Braun-Dullaeus, Ruediger C
Format: Article
Language:English
Subjects:
Animals
Antigens, Nuclear - genetics
Antigens, Nuclear - metabolism
Binding Sites
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cell Line, Tumor
Cell Proliferation - drug effects
Cercopithecus aethiops
Chromones - pharmacology
COS Cells
DNA Breaks, Double-Stranded
DNA Repair
DNA-Activated Protein Kinase - antagonists & inhibitors
DNA-Activated Protein Kinase - genetics
DNA-Activated Protein Kinase - metabolism
DNA-Binding Proteins - antagonists & inhibitors
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Estrogen Receptor alpha - genetics
Estrogen Receptor alpha - metabolism
Estrogens - metabolism
Estrogens - pharmacology
Humans
Immunoblotting
Immunoprecipitation
Ku Autoantigen
Morpholines - pharmacology
Phosphorylation - drug effects
Protein Binding - drug effects
RNA Interference
Ubiquitin - metabolism
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Summary:Estrogens are suggested to play a role in the development and progression of proliferative diseases such as breast cancer. Like other steroid hormone receptors, the estrogen receptor-alpha (ERalpha) is a substrate of protein kinases, and phosphorylation has profound effects on its function and activity. Given the importance of DNA-dependent protein kinase (DNA-PK) for DNA repair, cell cycle progression, and survival, we hypothesized that it modulates ERalpha signaling. Here we show that, upon estrogen stimulation, DNA-PK forms a complex with ERalpha in a breast cancer cell line (MELN). DNA-PK phosphorylates ERalpha at Ser-118. Phosphorylation resulted in stabilization of ERalpha protein as inhibition of DNA-PK resulted in its proteasomal degradation. Activation of DNA-PK by double-strand breaks or its inhibition by siRNA technology demonstrated that estrogen-induced ERalpha activation and cell cycle progression is, at least, partially dependent on DNA-PK.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E09-08-0724