The retinoblastoma protein modulates Tbx2 functional specificity.
The retinoblastoma protein modulates Tbx2 functional specificity.
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DOI：
10.1091/mbc.e09-12-1029
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发表时间：
2010-08-01
影响因子：
3.3
通讯作者：
Goding CR
中科院分区：
文献类型：
--
作者：
Vance KW;Shaw HM;Rodriguez M;Ott S;Goding CR
本研究证实Tbx2与Rb1结合。与Rb1的相互作用增加了Tbx2的dna结合活性，增强了Tbx2抑制转录的能力。结果表明，Tbx2可调节细胞分裂和DNA复制相关基因的表达，而Rb1可调节Tbx2靶基因的识别和特异性。Tbx2是一个与T-box dna结合域同源的转录因子大家族的成员。Tbx2通过其抑制衰老和促进侵袭的能力，在胚胎发育和癌症中发挥关键作用。尽管它很重要，但人们对Tbx2如何调控或如何实现靶基因特异性知之甚少。在这里，我们发现Tbx2特异性地与活性低磷酸化视网膜母细胞瘤蛋白（Rb1）相关，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因子，但不与Rb1相关蛋白p107或p130相关。与Rb1的相互作用直接映射到T-box的羧基末端，并增强Tbx2 DNA结合和转录抑制。对表达诱导显性负Tbx2（包括T-box和完整或突变的Rb1相互作用结构域）的黑色素瘤细胞的微阵列分析表明，Tbx2调节许多参与细胞周期控制的基因的表达，而破坏Rb1-Tbx2相互作用的突变也会影响Tbx2靶基因的选择性。综上所述，数据显示Rb1是Tbx2功能特异性的重要决定因素。
This study demonstrates that Tbx2 binds Rb1. The interaction with Rb1 increases Tbx2 DNA-binding activity and enhances the ability of Tbx2 to repress transcription. The results show that Tbx2 regulates the expression of genes involved in cell division and DNA replication and that Rb1 modulates Tbx2 target gene recognition and specificity. 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.