Department of Systems Biology, Biomedical Research Institute, University of Warwick, Coventry, CV4 7AL, United Kingdom.
Mol Biol Cell. 2010 Aug 1;21(15):2770-9. doi: 10.1091/mbc.E09-12-1029. Epub 2010 Jun 9.
Tbx2 is a member of a large family of transcription factors defined by homology to the T-box DNA-binding domain. Tbx2 plays a key role in embryonic development, and in cancer through its capacity to suppress senescence and promote invasiveness. Despite its importance, little is known of how Tbx2 is regulated or how it achieves target gene specificity. Here we show that Tbx2 specifically associates with active hypophosphorylated retinoblastoma protein (Rb1), a known regulator of many transcription factors involved in cell cycle progression and cellular differentiation, but not with the Rb1-related proteins p107 or p130. The interaction with Rb1 maps to a domain immediately carboxy-terminal to the T-box and enhances Tbx2 DNA binding and transcriptional repression. Microarray analysis of melanoma cells expressing inducible dominant-negative Tbx2, comprising the T-box and either an intact or mutated Rb1 interaction domain, shows that Tbx2 regulates the expression of many genes involved in cell cycle control and that a mutation which disrupts the Rb1-Tbx2 interaction also affects Tbx2 target gene selectivity. Taken together, the data show that Rb1 is an important determinant of Tbx2 functional specificity.
Tbx2 是转录因子大家族的成员，其定义是与 T 盒 DNA 结合域的同源性。Tbx2 在胚胎发育和癌症中发挥关键作用，因为它能够抑制衰老并促进侵袭性。尽管其重要性不言而喻，但人们对 Tbx2 的调节方式或如何实现靶基因特异性知之甚少。在这里，我们表明 Tbx2 特异性地与活性低磷酸化视网膜母细胞瘤蛋白（Rb1）结合，Rb1 是参与细胞周期进程和细胞分化的许多转录因子的已知调节剂，但与 Rb1 相关蛋白 p107 或 p130 不结合。与 Rb1 的相互作用定位于 T 盒羧基末端的一个结构域，可增强 Tbx2 的 DNA 结合和转录抑制活性。表达诱导型显性负性 Tbx2 的黑色素瘤细胞的微阵列分析，包括 T 盒和完整或突变的 Rb1 相互作用结构域，表明 Tbx2 调节许多参与细胞周期控制的基因的表达，并且破坏 Rb1-Tbx2 相互作用的突变也会影响 Tbx2 靶基因的选择性。总之，这些数据表明 Rb1 是 Tbx2 功能特异性的重要决定因素。
