Cooperative Transcriptional Activation by Klf4, Meis2, and Pbx1
Cooperative Transcriptional Activation by Klf4, Meis2, and Pbx1
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DOI：
10.1128/mcb.01456-10
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发表时间：
2011-09-01
影响因子：
5.3
通讯作者：
Wotton, David
中科院分区：
文献类型：
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作者：
Bjerke, Glen A.;Hyman-Walsh, Cathy;Wotton, David
Kruppel 样因子 Klf4 与肿瘤发生和维持干细胞多能性有关，并且 Klf4 既可以激活也可以抑制基因表达。我们表明，Pbx1 和 Meis2 同源域蛋白与 Klf4 相互作用，并且可以被募集到包含 Klf4 位点或 GC 盒以及相邻的 Meis 和 Pbx 位点的 DNA 元件。 Meis2d 和 Pbx1a 激活 p15(Ink4a) 和 E-钙粘蛋白的表达，依赖于 Meis2d 转录激活结构域。在 HepG2 细胞中，减少内源性 Meis2 或 Pbx1 的表达会降低 p15 基因的表达并增加进入 S 期的细胞数量。尽管所有三种蛋白质的 DNA 结合都有助于完全协同激活，但 Meis2 和 Pbx1 结合的序列要求是可变的。在 E-钙粘蛋白启动子中，完全激活需要 Pbx 样位点，而在 p15 启动子中，Klf4 位点似乎发挥主要作用。通过生物信息学搜索，我们鉴定了具有 Klf4、Meis2 和 Pbx1 保守结合位点的其他基因，并表明这些基因中至少有一些可以被 Klf4 和 Meis2/Pbx1 协同激活。我们提出了一个模型，其中带有 Klf4 位点的基因可以由 Meis2/Pbx1 和 Klf4 协同激活，主要依赖于 Klf4 的募集。这提供了一种通过多功能 Klf4 转录因子调节转录调控的机制。
The Kruppel-like factor Klf4 is implicated in tumorigenesis and maintaining stem cell pluripotency, and Klf4 can both activate and repress gene expression. We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or GC box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. In HepG2 cells, reducing expression of endogenous Meis2 or Pbx1 decreases p15 gene expression and increases the number of cells entering S phase. Although DNA binding by all three proteins contributes to full cooperative activation, the sequence requirements for binding by Meis2 and Pbx1 are variable. In the E-cadherin promoter, a Pbx-like site is required for full activation, whereas in the p15 promoter, the Klf4 site appears to play the major role. Through a bioinformatics search we identified additional genes with conserved binding sites for Klf4, Meis2, and Pbx1 and show that at least some of these genes can be activated cooperatively by Klf4 and Meis2/Pbx1. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4. This provides a mechanism to modulate transcriptional regulation by the multifunctional Klf4 transcription factor.