Wild type p53 transcriptionally represses the SALL2 transcription factor under genotoxic stress.
Wild type p53 transcriptionally represses the SALL2 transcription factor under genotoxic stress.
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DOI：
10.1371/journal.pone.0073817
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Pincheira R
中科院分区：
文献类型：
--
作者：
Farkas C;Martins CP;Escobar D;Hepp MI;Castro AF;Evan G;Gutiérrez JL;Warren R;Donner DB;Pincheira R
SALL2是Spalt基因家族的一员，是一种特征不明确的转录因子，在各种癌症中发现不受调节，这表明它在疾病中起作用。我们之前发现SALL2是一种新的神经营养因子受体相互作用蛋白，并表明它在神经元功能中起作用，这并不一定解释SALL2在癌症中为何或如何失调。已有证据表明，SALL2基因受WT1和AP4转录因子的调控。在这里，我们发现SALL2是p53肿瘤抑制蛋白的一个新的下游靶点。SALL2基因的生物信息学分析揭示了沿启动子区域的几个假定的p53半位点。在多种细胞系中，野生型p53过表达或基因毒性药物阿霉素诱导内源性p53均可抑制SALL2启动子活性。然而，在癌症患者肿瘤中经常发现的p53突变体R175H、R249S和R248W无法抑制SALL2启动子活性，这表明p53特异性结合DNA对SALL2的调控很重要。电泳迁移转移实验证实p53与Sall2启动子中一个已确定的p53半位点结合，染色质免疫沉淀分析证实p53与含有该半位点的Sall2启动子区域在体内相互作用。重要的是，通过使用表达完全依赖4-羟基他莫昔芬的p53变体的p53ERTAM敲入模型，我们发现p53激活在小鼠胚胎成纤维细胞（mef）和体内放射敏感组织的基因毒性细胞应激过程中降低了SALL2 RNA和蛋白质水平。因此，我们的发现表明，p53以一种特定于环境的方式抑制SALL2的表达，增加了对SALL2基因调控的理解，以及其在癌症中解除管制的潜在机制。
SALL2- a member of the Spalt gene family- is a poorly characterized transcription factor found deregulated in various cancers, which suggests it plays a role in the disease. We previously identified SALL2 as a novel interacting protein of neurotrophin receptors and showed that it plays a role in neuronal function, which does not necessarily explain why or how SALL2 is deregulated in cancer. Previous evidences indicate that SALL2 gene is regulated by the WT1 and AP4 transcription factors. Here, we identified SALL2 as a novel downstream target of the p53 tumor suppressor protein. Bioinformatic analysis of the SALL2 gene revealed several putative p53 half sites along the promoter region. Either overexpression of wild-type p53 or induction of the endogenous p53 by the genotoxic agent doxorubicin repressed SALL2 promoter activity in various cell lines. However R175H, R249S, and R248W p53 mutants, frequently found in the tumors of cancer patients, were unable to repress SALL2 promoter activity, suggesting that p53 specific binding to DNA is important for the regulation of SALL2. Electrophoretic mobility shift assay demonstrated binding of p53 to one of the identified p53 half sites in the Sall2 promoter, and chromatin immunoprecipitation analysis confirmed in vivo interaction of p53 with the promoter region of Sall2 containing this half site. Importantly, by using a p53ERTAM knockin model expressing a variant of p53 that is completely dependent on 4-hydroxy-tamoxifen for its activity, we show that p53 activation diminished SALL2 RNA and protein levels during genotoxic cellular stress in primary mouse embryo fibroblasts (MEFs) and radiosensitive tissues in vivo. Thus, our finding indicates that p53 represses SALL2 expression in a context-specific manner, adding knowledge to the understanding of SALL2 gene regulation, and to a potential mechanism for its deregulation in cancer.
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影响因子：
5.6
作者：
Henriquez, Berta;Hepp, Matias;Merino, Paola;Sepulveda, Hugo;Van Wijnen, Andre J.;Lian, Jane B.;Stein, Gary S.;Stein, Janet L.;Montecino, Martin
通讯作者：
Montecino, Martin
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影响因子：
9.2
作者：
Gu B;Zhu WG
通讯作者：
Zhu WG
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影响因子：
8
作者：
Huang, B.;Qu, Z.;Ong, C. W.;Tsang, Y-H N.;Xiao, G.;Shapiro, D.;Salto-Tellez, M.;Ito, K.;Ito, Y.;Chen, L-F
通讯作者：
Chen, L-F
影响因子：
30.8
作者：
Christophorou, MA;Martin-Zanca, D;Evan, GI
通讯作者：
Evan, GI
影响因子：
64.5
作者：
Godar S;Ince TA;Bell GW;Feldser D;Donaher JL;Bergh J;Liu A;Miu K;Watnick RS;Reinhardt F;McAllister SS;Jacks T;Weinberg RA
通讯作者：
Weinberg RA