Transcriptional Regulation of Serine/Threonine Protein Kinase (AKT) Genes by Glioma-associated Oncogene Homolog 1
Transcriptional Regulation of Serine/Threonine Protein Kinase (AKT) Genes by Glioma-associated Oncogene Homolog 1
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DOI：
10.1074/jbc.m112.425249
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发表时间：
2013-05-24
影响因子：
4.8
通讯作者：
Vega, Francisco
中科院分区：
文献类型：
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作者：
Agarwal, Nitin K.;Qu, Changju;Vega, Francisco
Hedgehog信号的异常激活已经在越来越多的癌症中被描述，包括恶性淋巴瘤。在这里，我们报告说，典型的刺猬信号调节AKT基因的转录表达，AKT1是GLI1的直接转录靶点。我们确定了两个假定的结合位点GLI1在AKT1启动子区，并确认其功能，使用染色质免疫沉淀，荧光素酶报告，和定点诱变试验。此外，我们提供的证据表明，GLI1有助于弥漫性大B细胞淋巴瘤（DLBCL）细胞的生存，这种作用部分是通过促进AKT基因的转录而发生的。这一发现是有趣的，因为在DLBCL中已经描述了AKT的组成性激活，但是解释这种淋巴瘤类型中AKT表达的致病因素还不完全清楚。总之，我们证明了在DLBCL中Hedgehog信号传导和AKT之间在转录水平上存在具有生物学意义的新型串扰。
Aberrant activation of Hedgehog signaling has been described in a growing number of cancers, including malignant lymphomas. Here, we report that canonical Hedgehog signaling modulates the transcriptional expression of AKT genes and that AKT1 is a direct transcriptional target of GLI1. We identified two putative binding sites for GLI1 in the AKT1 promoter region and confirmed their functionality using chromatin immunoprecipitation, luciferase reporter, and site-directed mutagenesis assays. Moreover, we provide evidence that GLI1 contributes to the survival of diffuse large B-cell lymphoma (DLBCL) cells and that this effect occurs in part through promotion of the transcription of AKT genes. This finding is of interest as constitutive activation of AKT has been described in DLBCL, but causative factors that explain AKT expression in this lymphoma type are not completely known. In summary, we demonstrated the existence of a novel cross-talk at the transcriptional level between Hedgehog signaling and AKT with biological significance in DLBCL.