Identification of Y-box binding protein 1 as a core regulator of MEK/ERK pathway-dependent gene signatures in colorectal cancer cells.
Identification of Y-box binding protein 1 as a core regulator of MEK/ERK pathway-dependent gene signatures in colorectal cancer cells.
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DOI：
10.1371/journal.pgen.1001231
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发表时间：
2010-12-02
期刊：
影响因子：
4.5
通讯作者：
Schäfer R
中科院分区：
文献类型：
--
作者：
Jürchott K;Kuban RJ;Krech T;Blüthgen N;Stein U;Walther W;Friese C;Kiełbasa SM;Ungethüm U;Lund P;Knösel T;Kemmner W;Morkel M;Fritzmann J;Schlag PM;Birchmeier W;Krueger T;Sperling S;Sers C;Royer HD;Herzel H;Schäfer R
在全基因组水平上，转录特征是疾病相关分子改变的不可缺少的相关信息来源。许多候选基因涉及疾病和预测因素，以及预后价值，已经从这种分子画像中推断出来，例如在癌症中。然而，对控制全球转录变化的调控原则的机械见解落后于大量的去调控基因的汇编。为了确定转录组改变的调节因子，我们使用了一种综合的方法，结合使用靶向受体酪氨酸激酶(RTK)/RAS/丝裂原激活蛋白激酶途径的抑制剂处理的结直肠癌细胞系的转录谱，共调节基因启动子中调控元件的计算预测，基于染色质和功能细胞的测定。我们确定了共同调控的增殖相关靶基因，这些靶基因对MAPK通路有反应。我们认识到E2F和NFY转录因子结合位点是这些通路应答基因中普遍存在的基序，并通过报告基因、凝胶转移和染色质免疫沉淀试验证实了Y-box结合蛋白1 （YBX1）的预测调节作用。我们还验证了mapk依赖性基因在结直肠癌中的标记，并提供了YBX1与结直肠癌患者预后不良相关的证据。这表明MEK/ erk依赖性、ybx1调控的靶基因参与了恶性特性的执行。使用微阵列同时分析癌症基因表达是一种标准方法，用于监测涉及肿瘤发生、引发恶性特性和临床行为的疾病相关修饰。然而，驱动这些变化的因素通常仍然难以捉摸。我们试图在培养的结直肠癌细胞中确定介导受体酪氨酸激酶/RAS癌蛋白通路转录作用的转录因子，这是一个经常激活的致癌信号系统。我们使用了一种结合分子和功能分析以及计算工具的综合方法来确定触发基因表达改变和调节细胞生长的调节因子。我们发现YBX1蛋白是高度保守的冷休克域转录因子家族的一员，作为RAS癌基因触发的信号效应的调节因子。通过芯片检测YBX1和YBX1应答靶基因的mrna表达，免疫组化检测YBX1蛋白在结直肠肿瘤中的表达。我们发现YBX1表达与结肠癌患者的不良临床预后相关。
Transcriptional signatures are an indispensible source of correlative information on disease-related molecular alterations on a genome-wide level. Numerous candidate genes involved in disease and in factors of predictive, as well as of prognostic, value have been deduced from such molecular portraits, e.g. in cancer. However, mechanistic insights into the regulatory principles governing global transcriptional changes are lagging behind extensive compilations of deregulated genes. To identify regulators of transcriptome alterations, we used an integrated approach combining transcriptional profiling of colorectal cancer cell lines treated with inhibitors targeting the receptor tyrosine kinase (RTK)/RAS/mitogen-activated protein kinase pathway, computational prediction of regulatory elements in promoters of co-regulated genes, chromatin-based and functional cellular assays. We identified commonly co-regulated, proliferation-associated target genes that respond to the MAPK pathway. We recognized E2F and NFY transcription factor binding sites as prevalent motifs in those pathway-responsive genes and confirmed the predicted regulatory role of Y-box binding protein 1 (YBX1) by reporter gene, gel shift, and chromatin immunoprecipitation assays. We also validated the MAPK-dependent gene signature in colorectal cancers and provided evidence for the association of YBX1 with poor prognosis in colorectal cancer patients. This suggests that MEK/ERK-dependent, YBX1-regulated target genes are involved in executing malignant properties. The simultaneous analysis of gene expression in cancer using microarrays is a standard approach for monitoring disease-related modifications involved in tumorigenesis, triggering malignant properties and clinical behavior. However, the factors that drive these alterations most often remain elusive. We sought to identify transcription factors that mediate the transcriptional effects of the receptor tyrosine kinase/RAS oncoprotein pathway, a frequently activated oncogenic signaling system, in cultured colorectal cancer cells. We used an integrated approach combining molecular and functional assays, as well as computational tools, to identify regulatory factors that trigger the alterations of gene expression and modulate cellular growth. We identified the YBX1 protein, a member of the highly conserved family of cold shock domain transcription factors, as a regulator of signaling effects triggered by the RAS cancer gene. Then we assayed the messenger RNA expression of YBX1 and YBX1-responsive target genes by interrogating microarrays, and also expression of the YBX1 protein by immunohistochemistry in colorectal tumors. We found that YBX1 expression is correlated with a bad clinical outcome in colon cancer patients.
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影响因子：
8
作者：
Astanehe, A.;Finkbeiner, M. R.;Dunn, S. E.
通讯作者：
Dunn, S. E.
影响因子：
14.9
作者：
Blüthgen N;Kiełbasa SM;Herzel H
通讯作者：
Herzel H
DOI：
10.1073/pnas.92.17.7686
发表时间：
1995-08-15
影响因子：
11.1
作者：
DUDLEY, DT;PANG, L;SALTIEL, AR
通讯作者：
SALTIEL, AR
影响因子：
8.4
作者：
Basaki, Yuji;Taguchi, Ken-ichi;Kuwano, Michihiko
通讯作者：
Kuwano, Michihiko
影响因子：
5.3
作者：
Evdokimova, V;Ruzanov, P;Sorensen, PHB
通讯作者：
Sorensen, PHB