Zwijsen R M, Buckle R S, Hijmans E M, Loomans C J, Bernards R
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
Genes Dev. 1998 Nov 15;12(22):3488-98. doi: 10.1101/gad.12.22.3488.
The estrogen receptor (ER) is an important regulator of growth and differentiation of breast epithelium. Transactivation by ER depends on a leucine-rich motif, which constitutes a ligand-regulated binding site for steroid receptor coactivators (SRCs). Cyclin D1 is frequently amplified in breast cancer and can activate ER through direct binding. We show here that cyclin D1 also interacts in a ligand-independent fashion with coactivators of the SRC-1 family through a motif that resembles the leucine-rich coactivator binding motif of nuclear receptors. By acting as a bridging factor between ER and SRCs, cyclin D1 can recruit SRC-family coactivators to ER in the absence of ligand. A cyclin D1 mutant that binds to ER but fails to recruit coactivators preferentially interferes with ER activation in breast cancer cells that have high levels of cyclin D1. These data support that cyclin D1 contributes significantly to ER activation in breast cancers in which the protein is overexpressed. Our present results reveal a novel route of coactivator recruitment to ER and establish a direct role for cyclin D1 in regulation of transcription.
雌激素受体（ER）是乳腺上皮细胞生长和分化的重要调节因子。ER的反式激活依赖于一个富含亮氨酸的基序，该基序构成了类固醇受体共激活因子（SRCs）的配体调节结合位点。细胞周期蛋白D1在乳腺癌中经常扩增，并且可以通过直接结合来激活ER。我们在此表明，细胞周期蛋白D1还通过一个类似于核受体富含亮氨酸的共激活因子结合基序的基序，以不依赖配体的方式与SRC-1家族的共激活因子相互作用。通过作为ER和SRCs之间的桥梁因子，细胞周期蛋白D1可以在没有配体的情况下将SRC家族共激活因子招募到ER。一个与ER结合但不能招募共激活因子的细胞周期蛋白D1突变体，在细胞周期蛋白D1水平高的乳腺癌细胞中优先干扰ER激活。这些数据支持细胞周期蛋白D1在该蛋白过度表达的乳腺癌中对ER激活有显著贡献。我们目前的结果揭示了一种将共激活因子招募到ER的新途径，并确立了细胞周期蛋白D1在转录调控中的直接作用。
