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 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.
Medunjanin
Senad
S
Internal Medicine, Department of Cardiology, Angiology, and Pneumology, Magdeburg University, 39120 Magdeburg, Germany. senad.medunjanin@med.ovgu.de
Weinert
Sönke
S
Schmeisser
Alexander
A
Mayer
Doris
D
Braun-Dullaeus
Ruediger C
RC
D000818:Animals; D034961:Antigens, Nuclear / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D002867:Chromones / Q000494:pharmacology; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D000072200:Ku Autoantigen; D009025:Morpholines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D025801:Ubiquitin / Q000378:metabolism
C479235:2-(morpholin-4-yl)benzo(h)chromen-4-one; D034961:Antigens, Nuclear; D002867:Chromones; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D004967:Estrogens; D009025:Morpholines; D025801:Ubiquitin; D051747:DNA-Activated Protein Kinase; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen