Sal-like protein 2 upregulates p16 expression through a proximal promoter element.
Sal-like protein 2 upregulates p16 expression through a proximal promoter element.
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DOI：
10.1111/cas.12606
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发表时间：
2015-03
期刊：
影响因子：
5.7
通讯作者：
Li D
中科院分区：
文献类型：
--
作者：
Wu Z;Cheng K;Shi L;Li Z;Negi H;Gao G;Kamle S;Li D
SAL样蛋白2(SALL2)是一种同源异型转录因子，可能是一种肿瘤抑制因子。我们先前已经证明SALL2激活肿瘤抑制基因p21的转录，并通过抑制细胞周期和诱导细胞凋亡来抑制肿瘤的发生。为了研究其他受SALL2调控的下游基因，我们分析了有和没有外源表达SALL2的mRNA表达谱的差异。我们通过基因表达阵列鉴定了1616个SALL2反应基因。P16INK4A和其他几个肿瘤相关基因的启动子-报告基因分析表明，SALL2对这些启动子的调控在两种主要形式的SALL2中没有显著差异，两种形式的SALL2具有交替的外显子1或外显子1a。进一步分析表明，SALL2诱导的p16启动子激活与SALL2的剂量相关。P16启动子的缺失和定点突变在p16转录起始点附近发现了一个共同的SALL2结合位点(GGGTGGG)，这是p16启动子激活的关键。最后，为了证实SALL2激活的p16表达在细胞周期调控中的意义，我们将SALL2表达载体与p16基因共转染SKOV3细胞，并将SALL2表达载体与针对p16的siRNA共转染ES-2细胞进行流式细胞仪分析。我们的结果表明，SALL2增强了p16基因对细胞周期进程的阻断，而p16与siRNA一起敲除了SALL2对细胞周期进程的大部分抑制。这些发现表明，SALL2通过它们的启动子针对包括p16在内的多个细胞周期调控因子，从而增加了对SALL2和p16基因调控的了解，以及SALL2放松调控如何促进癌症形成。
Sal-like protein 2 (Sall2), a homeotic transcription factor, is a putative tumor suppressor. We have previously shown that Sall2 activates the transcription of tumor suppressor gene p21 and suppresses tumorigenesis through cell cycle inhibition and induction of apoptosis. To investigate additional Sall2-regulated downstream genes, we analyzed the differences in mRNA expression profiles with and without exogenously expressed Sall2. We identified 1616 Sall2-responsive genes through gene expression arrays. Promoter-reporter assays of p16INK4A and several other tumor-related genes indicated that the Sall2 regulation of these promoters was not significantly different between the two major forms of Sall2 with alternative exon 1 or exon 1A. Additional analysis showed that Sall2-induced p16 promoter activation was Sall2 dose-dependent. Deletion and site-directed mutagenesis of the p16 promoter identified a consensus Sall2 binding site (GGGTGGG) proximal to the p16 transcription start site and was critical for p16 promoter activation. Finally, to confirm the significance of Sall2-activated p16 expression in cell cycle regulation, we co-transfected the SKOV3 cells with a Sall2 expression construct and a p16 minigene and also co-transfected the ES-2 cells with a Sall2 expression construct and the siRNA against p16 for flow cytometry analysis. Our results showed that Sall2 enhanced the p16 minigene blocking of cell cycle progression and p16 knockdown with siRNA abolished most of the Sall2 inhibition of cell cycle progression. These findings indicate that Sall2 targets multiple cell cycle regulators, including p16, through their promoters, adding knowledge to the understanding of Sall2 and p16 gene regulation, and how Sall2 deregulation may promote cancer formation.
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DOI：
10.1016/j.bbagrm.2011.02.002
发表时间：
2011-04
影响因子：
4.7
作者：
Gu, Hongcang;Li, Dawei;Sung, Chang K.;Yim, Hyungshin;Troke, Philip;Benjamin, Thomas
通讯作者：
Benjamin, Thomas
影响因子：
3.7
作者：
Farkas C;Martins CP;Escobar D;Hepp MI;Castro AF;Evan G;Gutiérrez JL;Warren R;Donner DB;Pincheira R
通讯作者：
Pincheira R
影响因子：
--
作者：
Yang, Jihua;Jiao, Shunchang
通讯作者：
Jiao, Shunchang
影响因子：
3.9
作者：
Lu Y;Zhang X;Zhang J
通讯作者：
Zhang J
影响因子：
3.7
作者：
Gärtner S;Gunesch A;Knyazeva T;Wolf P;Högel B;Eiermann W;Ullrich A;Knyazev P;Ataseven B
通讯作者：
Ataseven B