Id-1 activates Akt-mediated Wnt signaling and p27Kip1 phosphorylation through PTEN inhibition
Id-1 activates Akt-mediated Wnt signaling and p27Kip1 phosphorylation through PTEN inhibition
复制标题
DOI：
10.1038/onc.2008.451
复制
发表时间：
2009-02-01
期刊：
影响因子：
8
通讯作者：
Kong, G.
中科院分区：
文献类型：
--
作者：
Lee, J-Y;Kang, M-B;Kong, G.
分化抑制因子-1（Inhibitor of differentiation-1，Id-1）是一种公认的癌基因，通过抑制肿瘤抑制因子的活性和激活促生长通路来促进肿瘤的发生发展。在这里，我们表明，Id-1激活Akt途径，通过抑制磷酸酶和张力蛋白同源物10号染色体上删除（PTEN）转录下调p53。Id-1在转录水平上负调控p53和PTEN。在启动子序列缺失和染色质免疫沉淀试验中，Id-1降低了p53与PTEN启动子的结合，表明Id-1通过其p53调节来调节PTEN转录。这导致Akt在Ser 473处磷酸化并激活Akt介导的经典Wnt信号通路。糖原合成酶激酶-3 β在Ser 9的磷酸化、β-连环蛋白的稳定化和核定位、T细胞因子（TCF）/淋巴增强因子反式激活活性和细胞周期蛋白D1表达被Id-1增强。另一方面，Akt介导的p27（Kip 1）磷酸化在Thr 157和其胞质定位也增加Id-1过表达的MCF 7细胞。总之，我们的研究结果揭示了Id-1作为一种新的PTEN抑制剂，可以激活Akt通路及其下游效应子，Wnt/TCF通路和p27（Kip 1）磷酸化，并表明Id-1的致癌功能可能部分归因于其在人类乳腺癌发生中的PTEN抑制。
Inhibitor of differentiation-1 (Id-1) has been accepted as a putative oncogene to promote oncogenic processes through inactivation of tumor suppressors and activation of growth promoting pathways. Here, we show that Id-1 activates the Akt pathway by inhibition of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) transcription through downregulation of p53. Id-1 negatively regulated both p53 and PTEN at the transcriptional level. In promoter assay with serial deletion and chromatin immunoprecipitation assay, the binding of p53 to the PTEN promoter was reduced by Id-1, suggesting that Id-1 regulates PTEN transcription through its p53 modulation. This led to Akt phosphorylation at Ser473 and the activation of the Akt-mediated canonical Wnt signaling pathway. The glycogen synthase kinase-3 beta phosphorylation at Ser9, stabilization and nuclear localization of beta-catenin, T-cell factor (TCF)/lymphoid enhancer factor transactivation activity and cyclin D1 expression were enhanced by Id-1. On the other hand, Akt-mediated p27(Kip1) phosphorylation at Thr157 and its cytosolic localization were also increased in Id-1 overexpressing MCF7 cells. In conclusion, our results disclose Id-1 as a novel PTEN inhibitor that could activate the Akt pathway and its downstream effectors, the Wnt/TCF pathway and p27(Kip1) phosphorylation and suggest that the oncogenic function of Id-1 may be partly attributed to its PTEN inhibition in human breast carcinogenesis.