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Estrogen Receptor Accessory Factors in Breast Cancer Cells

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Final rept. 25 Jul 94-24 Jul 98

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The goal of this investigation was to identify proteins that associate with the ERa in a ligand- dependent manner and may therefore play a role in mediating the activity of the receptor. We have used the ligand binding domain of the ER ERa-LBD to capture proteins from mammalian cell extracts that associate with the ERa. One protein isolated by this technique is a kinase, able to bind and phosphorylate the ERa only in the presence of estrogen agonists such as estradiol. Using an array of chromatographic techniques and monitoring kinase activity, we have purified a stoichiometric complex of proteins to apparent homogeneity. Mass spectrometric sequencing has identified two of the protein components as Ca2calmodulin-dependent protein kinase II y and CamKII. Coimmunoprecipitation experiments show in vivo association of CamKII with ER upon stimulation of cells with estradiol and recent transfection experments suggest CamKll activity plays a role in transcriptional activation through the ERa. Additionally, site directed mutagenesis has defined the kinase binding site on the ER-LBD as a hydrophobic cleft previously implicated in recmitment of nuclear receptor coactivator proteins. Taken together, our data suggest that CamKII can serve as a novel modulator of ERa action. 1 MIIAD fl A

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  • Biochemistry
  • Medicine and Medical Research

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