The transcription factors Runx2 and estrogen receptor-alpha (ERalpha) are involved in numerous normal and disease processes, including postmenopausal osteoporosis and breast cancer. Using indirect immunofluorescence microscopy and pull-down techniques, we found them to colocalize and form complexes in a ligand-dependent manner. Estradiol-bound ERalpha strongly interacted with Runx2 directly through its DNA-binding domain and only indirectly through its N-terminal and ligand-binding domains. Runx2's amino acids 417-514, encompassing activation domain 3 and the nuclear matrix targeting sequence, were sufficient for interaction with ERalpha's DNA-binding domain. As a consequence of the interaction, Runx2's transcriptional activation activity was strongly repressed, as shown by reporter assays in COS7 cells, breast cancer cells, and late-stage MC3T3-E1 osteoblast cultures. Metaanalysis of gene expression in 779 breast cancer biopsies indicated negative correlation between the expression of ERalpha and Runx2 target genes. Selective ER modulators (SERM) induced ERalpha-Runx2 interactions but led to various functional outcomes. The regulation of Runx2 by ERalpha may play key roles in osteoblast and breast epithelial cell growth and differentiation; hence, modulation of Runx2 by native and synthetic ERalpha ligands offers new avenues in selective ER modulator evaluation and development.

译文

转录因子Runx2和雌激素受体 α (ERalpha) 参与许多正常和疾病过程,包括绝经后骨质疏松症和乳腺癌。使用间接免疫荧光显微镜和下拉技术,我们发现它们以配体依赖性方式共定位并形成复合物。雌二醇结合的ERalpha直接通过其DNA结合结构域与Runx2强烈相互作用,仅通过其N端和配体结合结构域间接相互作用。Runx2的氨基酸417-514,包括活化结构域3和核基质靶向序列,足以与ERalpha的DNA结合结构域相互作用。作为相互作用的结果,Runx2的转录激活活性被强烈抑制,如COS7细胞,乳腺癌细胞和晚期MC3T3-E1成骨细胞培养物中的报告分析所示。对779乳腺癌活检组织中基因表达的荟萃分析表明,ERalpha和Runx2靶基因的表达呈负相关。选择性ER调节剂 (SERM) 诱导ERalpha-Runx2相互作用,但导致各种功能结果。ERalpha对Runx2的调节可能在成骨细胞和乳腺上皮细胞的生长和分化中起关键作用; 因此,天然和合成的ERalpha配体对Runx2的调节为选择性ER调节剂的评估和开发提供了新的途径。

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