Nassa Giovanni, Tarallo Roberta, Guzzi Pietro H, Ferraro Lorenzo, Cirillo Francesca, Ravo Maria, Nola Ernesto, Baumann Marc, Nyman Tuula A, Cannataro Mario, Ambrosino Concetta, Weisz Alessandro
Department of General Pathology, Second University of Naples, Via L. De Crecchio 7, 80138 Napoli, Italy.
Mol Biosyst. 2011 Mar;7(3):667-76. doi: 10.1039/c0mb00145g. Epub 2010 Dec 20.
Estrogen Receptor alpha and beta (ER-α and -β) are members of the nuclear receptor family of transcriptional regulators with distinct roles in mediating estrogen dependent breast cancer cell growth and differentiation. Following activation by the hormone, these proteins undergo conformation changes and accumulate in the nucleus, where they bind to chromatin at regulatory sites as homo- and/or heterodimers and assemble in large multiprotein complexes. Although the two ERs share a conserved structure, they exert specific and distinct functional roles in normal and transformed mammary epithelial cells and other cell types. To investigate the molecular bases of such differences, we performed a comparative computational analysis of the nuclear interactomes of the two ER subtypes, exploiting two datasets of receptor interacting proteins identified in breast cancer cell nuclei by Tandem Affinity Purification for their ability to associate in vivo with ligand-activated ER-α and/or ER-β. These datasets comprise 498 proteins, of which only 70 are common to both ERs, suggesting that differences in the nature of the two ER interactomes are likely to sustain the distinct roles of the two receptor subtypes. Functional characterization of the two interactomes and their topological analysis, considering node degree and closeness of the networks, confirmed this possibility. Indeed, clustering and network dissection highlighted the presence of distinct and ER subtype-specific subnetworks endowed with defined functions. Altogether, these data provide new insights on the protein-protein interaction networks controlled by ER-α and -β that mediate their ability to transduce estrogen signaling in breast cancer cells.
雌激素受体α和β（ER-α和 -β）是核受体转录调节因子家族的成员，在介导雌激素依赖性乳腺癌细胞的生长和分化中具有不同作用。在被激素激活后，这些蛋白质会发生构象变化并在细胞核中积累，在那里它们作为同二聚体和/或异二聚体与染色质上的调节位点结合，并组装成大型多蛋白复合物。尽管两种雌激素受体具有保守结构，但它们在正常和转化的乳腺上皮细胞及其他细胞类型中发挥着特定且不同的功能作用。为了研究这些差异的分子基础，我们利用串联亲和纯化技术在乳腺癌细胞核中鉴定出的两个受体相互作用蛋白数据集，对两种雌激素受体亚型的核相互作用组进行了比较计算分析，以探究它们在体内与配体激活的ER-α和/或ER-β结合的能力。这些数据集包含498种蛋白质，其中只有70种是两种雌激素受体共有的，这表明两种雌激素受体相互作用组性质的差异可能维持了两种受体亚型的不同作用。考虑到网络的节点度和紧密性，对这两个相互作用组进行功能表征及其拓扑分析证实了这种可能性。事实上，聚类和网络剖析突出了具有特定功能的不同的、雌激素受体亚型特异性子网的存在。总之，这些数据为ER-α和 -β控制的蛋白质 - 蛋白质相互作用网络提供了新的见解，这些网络介导了它们在乳腺癌细胞中传导雌激素信号的能力。
