Regulation of proto-oncogene transcription, cell proliferation, and tumorigenesis in mice by PSF protein and a VL30 noncoding RNA
Regulation of proto-oncogene transcription, cell proliferation, and tumorigenesis in mice by PSF protein and a VL30 noncoding RNA
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PSF 蛋白和 VL30 非编码 RNA 对小鼠原癌基因转录、细胞增殖和肿瘤发生的调节
DOI：
10.1073/pnas.0909022106
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发表时间：
2009-09-29
影响因子：
11.1
通讯作者：
Song, Xu
中科院分区：
文献类型：
--
作者：
Wang, Gang;Cui, Ying;Song, Xu
我们描述了PSF蛋白和VL 30 -1 RNA（一种小鼠逆转录因子非编码RNA）在小鼠原癌基因转录、细胞增殖和肿瘤发生的可逆调节中的作用。实验涉及通过在强启动子的控制下阻断相应的编码基因来增加NIH/3 T3成纤维细胞和B16 F10黑素瘤细胞中PSF或VL 30 -1 RNA的表达，或通过阻断引起PSF mRNA或VL 30 -1 RNA降解的shRNA构建体来降低表达。结果如下：（i）PSF与原癌基因Rab 23结合，抑制转录，并且VL 30 -1 RNA与Rab 23结合并从Rab 23释放PSF，激活转录;（ii）增加PSF的表达或降低VL 30 -1 RNA的表达抑制培养物中的细胞增殖和小鼠中的肿瘤发生;和（iii）降低PSF的表达或增加VL 30 -1 RNA的表达促进培养物中的细胞增殖和小鼠中的肿瘤发生。这些结果表明，PSF是一个主要的肿瘤抑制蛋白和VL 30 -1 RNA是一个主要的肿瘤促进RNA在小鼠中。尽管VL 30 -1 RNA可以整合到细胞基因组中，但VL 30 -1 RNA的肿瘤促进作用涉及对基因转录的反式效应而不是顺式效应。小鼠肿瘤系中VL 30 -1 RNA的表达比小鼠成纤维细胞或成肌细胞系高5- 8倍，而肿瘤系中PSF mRNA的表达不降低，表明肿瘤发生是由VL 30 -1 RNA的增加而不是PSF的减少驱动的。类似的调节机制在人类细胞中起作用，除了人PSF结合RNA取代不在人类基因组中编码的VL 30 -1 RNA。我们提出，PSF蛋白和PSF结合RNA在哺乳动物细胞增殖和肿瘤发生的可逆调节中具有核心作用，并且在肿瘤细胞中增加PSF表达或减少PSF结合RNA表达是癌症的潜在治疗策略。
We describe the role of PSF protein and VL30-1 RNA, a mouse retroelement noncoding RNA, in the reversible regulation of protooncogene transcription, cell proliferation, and tumorigenesis in mice. The experiments involved increasing expression of PSF or VL30-1 RNA in NIH/3T3 fibroblast cells and B16F10 melanoma cells by transfecting the respective coding genes under control of a strong promoter or decreasing expression by transfecting a shRNA construct that causes degradation of PSF mRNA or VL30-1 RNA. The results are as follows: (i) PSF binds to the proto-oncogene Rab23, repressing transcription, and VL30-1 RNA binds and releases PSF from Rab23, activating transcription; (ii) increasing expression of PSF or decreasing expression of VL30-1 RNA suppresses cell proliferation in culture and tumorigenesis in mice; and (iii) decreasing expression of PSF or increasing expression of VL30-1 RNA promotes cell proliferation in culture and tumorigenesis in mice. These results indicate that PSF is a major tumor-suppressor protein and VL30-1 RNA is a major tumor-promoter RNA in mice. Although VL30-1 RNA can integrate into the cell genome, tumor promotion by VL30-1 RNA involves a trans effect rather than a cis effect on gene transcription. Expression of VL30-1 RNA is 5- to 8-fold higher in mouse tumor lines than in mouse fibroblast or myoblast lines, whereas expression of PSF mRNA does not decrease in the tumor lines, suggesting that tumorigenesis is driven by an increase of VL30-1 RNA rather than a decrease of PSF. A similar regulatory mechanism functions in human cells, except that human PSF-binding RNAs replace VL30-1 RNA, which is not encoded in the human genome. We propose that PSF protein and PSF-binding RNAs have a central role in the reversible regulation of mammalian cell proliferation and tumorigenesis and that increasing PSF expression or decreasing PSF-binding RNA expression in tumor cells is a potential therapeutic strategy for cancer.