PIM3原癌基因激酶是不同EWS/ETS癌蛋白的常见转录靶点。
PIM3 proto-oncogene kinase is a common transcriptional target of divergent EWS/ETS oncoproteins.
作者信息
Deneen Benjamin, Welford Scott M, Ho Thu, Hernandez Felicia, Kurland Irwin, Denny Christopher T
机构信息
Molecular Biology Institute, University of California-Los Angeles, Los Angeles, California 90095, USA.
出版信息
Mol Cell Biol. 2003 Jun;23(11):3897-908. doi: 10.1128/MCB.23.11.3897-3908.2003.
Despite significant structural diversity, present evidence suggests that EWS/ETS fusion proteins promote oncogenesis by transcriptionally modulating a common set of target genes. In order to identify these genes, microarray expression analyses were performed on NIH 3T3 polyclonal populations expressing one of three EWS/ETS fusion genes. The majority of these genes can be grouped into seven functional categories, including cellular metabolism and signal transduction. The biologic significance of these target genes was pursued. The effects of modulating genes involved in metabolism were assessed by flux studies and demonstrated shifts in glucose utilization and lactate production as a result of EWS/FLI1 expression. The proto-oncogene coding for serine/threonine kinase PIM3 was found to one of several genes encoding signal transduction proteins that were up-regulated by EWS/ETS fusions. PIM3 was found to be expressed in a panel of human Ewing's family tumor cell lines. Forced expression of PIM3 promoted anchorage-independent growth. Coexpression of a kinase-deficient PIM3 mutant attenuated EWS/FLI1-mediated NIH 3T3 tumorigenesis in immunodeficent mice.
尽管存在显著的结构多样性，但目前的证据表明，EWS/ETS融合蛋白通过转录调控一组共同的靶基因来促进肿瘤发生。为了鉴定这些基因，对表达三种EWS/ETS融合基因之一的NIH 3T3多克隆群体进行了微阵列表达分析。这些基因中的大多数可分为七个功能类别，包括细胞代谢和信号转导。对这些靶基因的生物学意义进行了研究。通过通量研究评估了调节参与代谢的基因的作用，并证明了由于EWS/FLI1表达导致葡萄糖利用和乳酸产生的变化。发现编码丝氨酸/苏氨酸激酶PIM3的原癌基因是几种编码信号转导蛋白的基因之一，这些基因被EWS/ETS融合上调。发现PIM3在一组人类尤因家族肿瘤细胞系中表达。PIM3的强制表达促进了不依赖贴壁的生长。激酶缺陷型PIM3突变体的共表达减弱了免疫缺陷小鼠中EWS/FLI1介导的NIH 3T3肿瘤发生。
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