Identification of SULF2 as a Novel Transcriptional Target of p53 by Use of Integrated Genomic Analyses
Identification of SULF2 as a Novel Transcriptional Target of p53 by Use of Integrated Genomic Analyses
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DOI：
10.1158/0008-5472.can-08-2742
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发表时间：
2009-02-15
期刊：
影响因子：
11.2
通讯作者：
Cleary, Michele A.
中科院分区：
文献类型：
--
作者：
Chau, B. Nelson;Diaz, Robert L.;Cleary, Michele A.
微阵列分析已用于鉴定许多转录因子的靶标。然而，响应于转录因子扰动的基因表达变化揭示了直接的转录靶点和次级基因调控。通过整合RNA干扰、基因表达谱分析和染色质免疫沉淀技术，我们确定了一组32个肿瘤抑制基因p53的直接转录靶点。在这32个基因中，11目前不与核心p53途径相关。从这些新的途径成员中，我们专注于了解p53和SULF 2之间的联系，SULF 2编码细胞外硫酸乙酰肝素6-O-endosulfatase，其调节生长因子与其同源受体的结合，并已被证明具有肿瘤抑制剂的功能。p53的遗传和药理学干扰直接影响SULF 2的表达，与TP 53的沉默类似，RNA干扰介导的SULF 2抑制导致细胞对遗传毒性应激的衰老反应受损。因此，我们的综合基因组方法导致了p53网络生物学的新介质的鉴定。[Cancer Res 2009;69（4）：1368-74]
Microarray analysis has been useful for identifying the targets of many transcription factors. However, gene expression changes in response to transcription factor perturbation reveal both direct transcriptional targets and secondary gene regulation. By integrating RNA interference, gene expression profiling, and chromatin immunoprecipitation technologies, we identified a set of 32 direct transcriptional targets of the tumor suppressor p53. Of these 32 genes, I I are not currently associated with the core p53 pathway. From among these novel pathway members, we focused on understanding the connection between p53 and SULF2, which encodes an extracellular heparan sulfate 6-O-endosulfatase that modulates the binding of growth factors to their cognate receptors and that has been shown to function as a tumor suppressor. Genetic and pharmacologic perturbation of p53 directly influences SULF2 expression, and similar to silencing of TP53, RNA interference-mediated suppression of SULF2 results in an impaired senescence response of cells to genotoxic stress. Thus, our integrated genomic approach has led to the identification of a novel mediator of p53 network biology. [Cancer Res 2009;69(4):1368-74]