A WNT/p21 Circuit Directed by the C-Clamp, a Sequence-Specific DNA Binding Domain in TCFs
A WNT/p21 Circuit Directed by the C-Clamp, a Sequence-Specific DNA Binding Domain in TCFs
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DOI：
10.1128/mcb.06769-11
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发表时间：
2012-09-01
影响因子：
5.3
通讯作者：
Waterman, Marian L.
中科院分区：
文献类型：
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作者：
Hoverter, Nate P.;Ting, Ju-Hui;Waterman, Marian L.
淋巴增强因子1/T细胞因子（LEF/TCF）家族转录因子是WNT信号通路的下游效应子，其驱动结肠肿瘤发生。LEF/TCF具有结合Wnt应答元件（WRE）的DNA序列特异性高迁移率族（HMG）盒。TCF的“E尾”同种型被选择性剪接以包括称为C-夹的第二DNA结合结构域。我们发现，诱导显性负C-钳TCF 1（dnTCF 1 E）的版本诱导p21的表达和停滞在DLD 1结肠癌细胞的生长。诱导的C-钳突变体没有有效地诱导p21，也没有停止细胞生长。微阵列分析显示，野生型dnTCF 1 E（dnTCF 1 E（WT））对p21的诱导与多种p21抑制因子表达的减少相关，这些抑制因子在转录（SP 5，YAP 1和RUNX 1），RNA稳定性（MSI 2）和蛋白质稳定性（CUL 4A）的多个水平上起作用。我们表明，C-钳是一个序列特异性的DNA结合结构域，可以与WRE上游或下游的5 '-RCCG-3'元件接触。C-clamp-RCCG相互作用对于TCF 1 E介导的p21连接的靶基因启动子的转录调控至关重要。我们的研究结果表明，快速响应WNT/p21电路是由C-钳靶基因选择驱动的。
The lymphoid enhancer factor 1/T cell factor (LEF/TCF) family of transcription factors are downstream effectors of the WNT signaling pathway, which drives colon tumorigenesis. LEF/TCFs have a DNA sequence-specific high-mobility group (HMG) box that binds Wnt response elements (WREs). The "E tail" isoforms of TCFs are alternatively spliced to include a second DNA binding domain called the C-clamp. We show that induction of a dominant negative C-clamp version of TCF1 (dnTCF1E) induces p21 expression and a stall in the growth of DLD1 colon cancer cells. Induction of a C-clamp mutant did not efficiently induce p21, nor did it stall cell growth. Microarray analysis revealed that induction of p21 by wild-type dnTCF1E (dnTCF1E(WT)) correlated with a decrease in expression of multiple p21 suppressors that act at multiple levels from transcription (SP5, YAP1, and RUNX1), RNA stability (MSI2), and protein stability (CUL4A). We show that the C-clamp is a sequence-specific DNA binding domain that can make contacts with 5'-RCCG-3' elements upstream or downstream of WREs. The C-clamp-RCCG interaction was critical for TCF1E-mediated transcriptional control of p21-connected target gene promoters. Our results indicate that a rapid-response WNT/p21 circuit is driven by C-clamp target gene selection.