PITX2 and β-catenin interactions regulate lef-1 isoform expression
PITX2 and β-catenin interactions regulate lef-1 isoform expression
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DOI：
10.1128/mcb.00315-07
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发表时间：
2007-11-01
影响因子：
5.3
通讯作者：
Amendt, Brad A.
中科院分区：
文献类型：
--
作者：
Amen, Melanie;Liu, Xiaoming;Amendt, Brad A.
在Wnt信号通路中，left -1和PITX2通过招募和与β -连环蛋白相互作用来激活靶基因。染色质免疫沉淀（ChIP）检测鉴定了left -1启动子是PITX2的下游靶点。由2.5 kb的LEF-1启动子驱动表达LacZ的转基因小鼠表明，其在牙齿上皮中的表达与内源性LEF-1 FL上皮的表达相关。PITX2同工型调节了LEF-1启动子，β -连环蛋白与PITX2和LEF-1同工型联合可协同增强LEF-1启动子的激活。PITX2增强内源性β -catenin全长依赖的左侧-1亚型（左侧-1 FL）的表达，同时降低n端截断的β -catenin独立亚型的表达。我们的研究揭示了PITX2、left -1和β -catenin之间的一种新的相互作用，其中left -1 β -catenin结合域在其与PITX2的相互作用中是必不可少的。PITX2与left -1蛋白中的两个位点相互作用。此外，β -catenin与PITX2同源结构域相互作用，而left - i与PITX2 c端尾部相互作用。left - i和P-catenin通过两个不同的位点同时独立地与PITX2相互作用，调节PITX2的转录活性。这些数据支持PITX2在细胞增殖、迁移和细胞分裂中的作用，通过不同的left -1异构体表达以及与left -1和β -连环蛋白的相互作用。
Lef-1 and PITX2 function in the Wnt signaling pathway by recruiting and interacting with beta-catenin to activate target genes. Chromatin immunoprecipitation (ChIP) assays identified the Lef-1 promoter as a PITX2 downstream target. Transgenic mice expressing LacZ driven by the 2.5-kb LEF-1 promoter demonstrated expression in the tooth epithelium correlated with endogenous Lef-1 FL epithelial expression. PITX2 isoforms regulate the LEF-1 promoter, and beta-catenin synergistically enhanced activation of the LEF-1 promoter in combination with PITX2 and Lef-1 isoforms. PITX2 enhances endogenous expression of the full-length beta-catenin-dependent Lef-1 isoform (Lef-1 FL) while decreasing expression of the N-terminally truncated beta-catenin-independent isoform. Our research revealed a novel interaction between PITX2, Lef-1, and beta-catenin in which the Lef-1 beta-catenin binding domain is dispensable for its interaction with PITX2. PITX2 interacts with two sites within the Lef-1 protein. Furthermore, beta-catenin interacts with the PITX2 homeodomain and Lef-I interacts with the PITX2 C-terminal tail. Lef-I and P-catenin interact simultaneously and independently with PITX2 through two different sites to regulate PITX2 transcriptional activity. These data support a role for PITX2 in cell proliferation, migration, and cell division through differential Lef-1 isoform expression and interactions with Lef-1 and beta-catenin.