Podoplanin is a novel Fos target gene in skin carcinogenesis
Podoplanin is a novel Fos target gene in skin carcinogenesis
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DOI：
10.1158/0008-5472.can-08-0299
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发表时间：
2008-09-01
期刊：
影响因子：
11.2
通讯作者：
Hess, Jochen
中科院分区：
文献类型：
--
作者：
Durchdewald, Moritz;Guinea-Viniegra, Juan;Hess, Jochen
癌基因转录因子激活蛋白(A-P-1，主要由Jun和Fos蛋白组成)的表达和功能是角质形成细胞在体外发生肿瘤转化和体内促癌及恶性进展所必需的。在这里，我们描述了372个差异表达基因的鉴定，比较了K5-SOS-F转基因小鼠的皮肤肿瘤样本(Fos(f/f)SOS+)和角质形成细胞中c-Fos特异缺失的动物(Fos(Delta EP)SOS+)的样本。用肿瘤样本和肿瘤促进剂12-O-十四烷基佛波醇-13-醋酸酯(TPA)处理的小鼠背部皮肤进行实时定量PCR分析，证实了所选基因的FOS依赖转录。Pdpn是差异表达最多的基因之一，编码小粘蛋白样糖蛋白Pdpn，它的表达与小鼠肿瘤模型系统和人类癌症的恶性进展相关。我们在化学诱导的小鼠皮肤肿瘤中发现了Pdpn和Fos的表达，并且对Pdpn基因启动子的详细分析表明，在Fos缺陷的情况下，Pdpn和Fos的活性受损。小鼠胚胎成纤维细胞，可通过异位表达Fos进行修复。染色质免疫沉淀表明，Fos蛋白直接与Pdpn启动子V结合，凝胶迁移率改变分析表明，在近端启动子的TPA反应元件类似基序处有TPA诱导的复合体。总之，我们可以在一个成熟的皮肤肿瘤模型中定义一个依赖于Fos的遗传程序。对这些新靶基因的系统分析将指导ITS阐明AP-1调控的通路的分子机制，这些通路与肿瘤转化和/或恶性进展密切相关。
Expression and function of the oncogenic transcription factor activator protein (A-P-1; mainly composed of Jun and Fos proteins) is required for neoplastic transformation of keratinocytes in vitro and tumor promotion as well as malignant progression in vivo. Here, we describe the identification of 372 differentially expressed genes comparing skin tumor samples of K5-SOS-F transgenic mice (Fos(f/f) SOS+) with samples derived from animals with a specific deletion of c-Fos in keratinocytes (Fos(Delta ep) SOS+). Fos-dependent transcription of selected genes was confirmed by quantitative real-time PCR analysis using tumor samples and mouse back skin treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). One of the most differentially expressed genes encodes the small mucin-like glycoprotein Podoplanin (Pdpn), whose expression correlates with malignant progression in mouse tumor model systems and human cancer. We found Pdpn and Fos expression in chemically induced mouse skin tumors, and detailed analysis of the Pdpn gene promoter revealed impaired activity in Fos-deficient. mouse embryonic fibroblasts, which could be restored by ectopic Fos expression. Direct Fos protein binding to the Pdpn promoter v.,as shown by chromatin immunoprecipitation and a TPA-induced complex at a TPA-responsive element-like motif in the proximal promoter was identified by electrophoretic mobility shift assays. In summary, we could define a Fos-dependent genetic program in a well-establisited model of skin tumors. Systematic analysis of these novel target genes will guide its in elucidating the molecular mechanisms of AP-1-regulated pathways that are critically implicated in neoplastic transformation and/or malignant progression.