Modulation of Runx2 Activity by Estrogen Receptor-α: Implications for Osteoporosis and Breast Cancer
Modulation of Runx2 Activity by Estrogen Receptor-α: Implications for Osteoporosis and Breast Cancer
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DOI：
10.1210/en.2008-0680
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发表时间：
2008-12-01
期刊：
影响因子：
4.8
通讯作者：
Frenkel, Baruch
中科院分区：
文献类型：
--
作者：
Khalid, Omar;Baniwal, Sanjeev K.;Frenkel, Baruch
转录因子Runx 2和雌激素受体-α（ER α）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，我们发现他们共定位，并形成复合物的配体依赖性的方式。雌二醇结合的ER α通过其DNA结合结构域直接与Runx 2强烈相互作用，并且仅通过其N-末端和配体结合结构域间接与Runx 2相互作用。Runx 2的氨基酸417-514，包括激活结构域3和核基质靶向序列，足以与ER α的DNA结合结构域相互作用。作为相互作用的结果，Runx 2的转录激活活性被强烈抑制，如在COS 7细胞、乳腺癌细胞和晚期MC 3 T3-E1成骨细胞培养物中的报告基因测定所示。对779例乳腺癌活检组织基因表达的荟萃分析表明，ER α和Runx 2靶基因的表达呈负相关。选择性ER调节剂（SERM）诱导ER α-Runx 2相互作用，但导致各种功能结果。ER α对Runx 2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ER α配体对Runx 2的调节为选择性ER调节剂的评价和开发提供了新的途径。（内分泌学149：5984-5995，2008）
The transcription factors Runx2 and estrogen receptor-alpha (ER alpha) 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 ER alpha 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 ER alpha'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 ER alpha and Runx2 target genes. Selective ER modulators (SERM) induced ER alpha-Runx2 interactions but led to various functional outcomes. The regulation of Runx2 by ER alpha may play key roles in osteoblast and breast epithelial cell growth and differentiation; hence, modulation of Runx2 by native and synthetic ER alpha ligands offers new avenues in selective ER modulator evaluation and development. (Endocrinology 149: 5984-5995, 2008)