Physical and functional cooperation between AP-1 and β-catenin for the regulation of TCF-dependent genes
Physical and functional cooperation between AP-1 and β-catenin for the regulation of TCF-dependent genes
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DOI：
10.1038/sj.onc.1210133
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发表时间：
2007-05-01
期刊：
影响因子：
8
通讯作者：
Bernuau, D.
中科院分区：
文献类型：
--
作者：
Toualbi, K.;Guller, M. C.;Bernuau, D.
细胞质β-连环蛋白的稳定是多种癌症的标志。稳定的β-连环蛋白能够易位到细胞核，在那里它充当T细胞因子（TCF）调节基因的转录激活因子。β-连环蛋白可以与许多信号级联交叉作用以激活靶基因。β-连环蛋白是否与AP-1（肿瘤发生过程中激活的另一种转录复合物）合作尚未完全阐明。我们表明，α-连环蛋白与c-Jun和c-os. GST下拉实验表明，与c-Jun的DNA结合结构域和β-连环蛋白的C-末端结构域与c-Fos的N-末端结构域的b-连环蛋白的犰狳重复结构域的物理协会。启动子研究表明，AP-1的过表达激活两个β-连环蛋白靶基因，细胞周期蛋白D1和c-myc的转录，通过一种机制独立于AP-1位点，并完全依赖于TCF结合位点。我们进一步证明，AP-1/β-连环蛋白协同作用参与血清诱导的细胞周期蛋白D1转录激活。我们确定了细胞周期蛋白D1启动子上的TCF结合位点，其在体内结合由血清诱导的复合物，所述复合物含有β-连环蛋白、TCF 4、c-Fos、c-Jun、JunB和JunD。这两个信号级联之间的相互作用的新机制可能有助于恶性肿瘤的增强。
Stabilization of cytoplasmic beta-catenin is a hallmark of a variety of cancers. The stabilized beta-catenin is able to translocate to the nucleus, where it acts as a transcriptional activator of T-cell factor (TCF)-regulated genes. beta-Catenin may cross-talk with many signalling cascades to activate target genes. Whether beta-catenin cooperates with AP-1, another transcriptional complex activated during tumorigenesis is not fully clarified. We show that alpha-catenin co-immunoprecipitates with c-Jun and c- os. GST pull-down experiments indicate a physical association of the armadillo repeat domain of b-catenin with the DNA-binding domain of c-Jun and of the C-terminal domain of beta- catenin with the N-terminal domain of c-Fos. Promoter studies indicate that overexpression of AP-1 activates the transcription of two beta-catenin target genes, cyclin D1 and c-myc, by a mechanism independent of the AP-1 site, and fully dependent on the TCF-binding site. We further demonstrate that AP-1/beta-catenin synergism is involved during serum-induced cyclin D1 transcriptional activation. We identify a TCF-binding site on the cyclin D1 promoter which binds in vivo a complex induced by serum, containing beta- catenin, TCF4, c-Fos, c-Jun, JunB and JunD. This novel mechanism of interaction between two signalling cascades might contribute to the potentiation of malignancy.