Identification of Tcf-4 as a transcriptional target of p53 signalling
Identification of Tcf-4 as a transcriptional target of p53 signalling
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DOI：
10.1038/sj.onc.1207464
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发表时间：
2004-04-22
期刊：
影响因子：
8
通讯作者：
Engeland, K
中科院分区：
文献类型：
--
作者：
Rother, K;Johne, C;Engeland, K
T细胞因子（Tcf）-4是传递Wnt/β-连环蛋白信号的主要转录因子。肿瘤抑制蛋白p53作为转录因子参与细胞周期阻滞和凋亡诱导。p53和Wnt/β-连环蛋白信号网络中组分的突变在肿瘤形成中起作用。在这里，我们确定Tcf-4基因作为p53的下游效应子。在tet关闭调节的人结肠细胞系统中诱导野生型p53导致Tcf-4 mRNA和蛋白水平的降低。此外，Tcf-4靶基因uPAR的mRNA在p53诱导后下调。由Tcf-4启动子控制的荧光素酶报告基因的表达被野生型p53抑制，但不被DNA结合缺陷的p53突变体抑制。这种调节在不同来源的细胞系中可见。这些发现直接链接Wnt/β-连环蛋白信号和p53肿瘤抑制功能，并可能提供一种机制，通过这种机制，p53功能的丧失有助于结肠肿瘤中腺瘤/癌序列的进展。此外，由于Tcf-4在许多组织中表达，并且在几种不同的细胞类型中观察到p53对Tcf-4的下调，因此这种调节可能在所有可表达p53和Tcf-4的组织的增殖控制中起作用。
T-cell factor (Tcf)-4 is a main transcription factor to pass on Wnt/beta-catenin signalling. The tumour suppressor protein p53 contributes as a transcription factor to cell-cycle arrest and apoptosis induction. Mutations of components in p53 and Wnt/beta-catenin signalling networks play a part in tumour formation. Here, we identify the Tcf-4 gene as a downstream effector of p53. Induction of wild-type p53 in a tet-off regulated human colon cell system leads to the reduction of Tcf-4 mRNA and protein levels. Also, mRNA of the Tcf-4 target gene uPAR is downregulated after p53 induction. Expression of a luciferase reporter controlled by the Tcf-4 promoter is repressed by wild-type p53, but not by a p53 mutant deficient in DNA binding. Such a regulation is seen in cell lines of different origin. These findings directly link Wnt/beta-catenin signalling and p53 tumour suppressor function and may provide a mechanism by which loss of p53 function contributes to progression in the adenoma/carcinoma sequence in colon tumours. Furthermore, since Tcf-4 is expressed in many tissues and downregulation of Tcf-4 by p53 is seen in several different cell types, this regulation likely plays a role in proliferation control of all tissues that can express p53 and Tcf-4.