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无Ras成纤维细胞转录组中可逆的、相互关联的mRNA和miRNA表达模式：功能及机制意义

Reversible, interrelated mRNA and miRNA expression patterns in the transcriptome of Rasless fibroblasts: functional and mechanistic implications.

作者信息

Azrak Sami S, Ginel-Picardo Alicia, Drosten Matthias, Barbacid Mariano, Santos Eugenio

机构信息

Centro de Investigacion del Cancer, IBMCC (CSIC-USAL), University of Salamanca, Campus Unamuno, 37007, Salamanca, Spain.

出版信息

BMC Genomics. 2013 Oct 25;14:731. doi: 10.1186/1471-2164-14-731.

DOI:10.1186/1471-2164-14-731
PMID:24156637
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4007593/
Abstract

BACKGROUND: 4-Hydroxy-tamoxifen (4OHT) triggers Cre-mediated K-Ras removal in [H-Ras-/-; N-Ras-/-; K-Ras lox/lox; RERT ert/ert] fibroblasts, generating growth-arrested "Rasless" MEFs which are able to recover their proliferative ability after ectopic expression of Ras oncoproteins or constitutively active BRAF or MEK1. RESULTS: Comparison of the transcriptional profiles of Rasless fibroblasts with those of MEFs lacking only H-Ras and N-Ras identified a series of differentially expressed mRNAs and microRNAs specifically linked to the disappearance of K-Ras from these cells. The rescue of cell cycle progression in Rasless cells by activated BRAF or MEK1 resulted in the reversal of most such transcriptional mRNA and microRNA alterations.Functional analysis of the differentially expressed mRNAs uncovered a significant enrichment in the components of pathways regulating cell division, DNA/RNA processing and response to DNA damage. Consistent with G1/S blockade, Rasless cells displayed repression of a series of cell cycle-related genes, including Cyclins, Cyclin-dependent kinases, Myc and E2F transcription targets, and upregulation of Cyclin-dependent kinase inhibitors. The profile of differentially expressed microRNAs included a specific set of oncomiR families and clusters (repressed miR-17 ~ 92, miR-106a ~ 363, miR-106b ~ 25, miR-212 ~ 132, miR-183 ~ 182, and upregulated miR-335) known for their ability to target a specific set of cellular regulators and checkpoint sensors (including Rb, E2F and Cdkns) able to modulate the interplay between the pro- and anti-proliferative or stress-response pathways that are reversibly altered in Rasless cells. CONCLUSIONS: Our data suggest that the reversible proliferation phenotype of Rasless cells is the pleiotropic result of interplay among distinct pro- and anti-proliferative, and stress-response pathways modulated by a regulatory circuitry constituted by a specific set of differentially expressed mRNAs and microRNAs and preferentially targeting two cross-talking signalling axes: Myc-Rb-E2F-dependent and Cdkns-p53-dependent pathways.

摘要

背景：4-羟基他莫昔芬（4OHT）可在[H-Ras-/-; N-Ras-/-; K-Ras lox/lox; RERT ert/ert]成纤维细胞中触发Cre介导的K-Ras去除，产生生长停滞的“无Ras”MEF，这些细胞在异位表达Ras癌蛋白、组成型活性BRAF或MEK1后能够恢复其增殖能力。 结果：将无Ras成纤维细胞的转录谱与仅缺乏H-Ras和N-Ras的MEF的转录谱进行比较，鉴定出一系列差异表达的mRNA和microRNA，它们与这些细胞中K-Ras的消失特异性相关。活化的BRAF或MEK1挽救无Ras细胞中的细胞周期进程，导致大多数此类转录mRNA和microRNA改变的逆转。对差异表达mRNA的功能分析发现，调节细胞分裂、DNA/RNA加工和对DNA损伤反应的途径的成分显著富集。与G1/S阻滞一致，无Ras细胞表现出一系列细胞周期相关基因的抑制，包括细胞周期蛋白、细胞周期蛋白依赖性激酶、Myc和E2F转录靶点，以及细胞周期蛋白依赖性激酶抑制剂的上调。差异表达的microRNA谱包括一组特定的致癌miRNA家族和簇（抑制的miR-1792、miR-106a363、miR-106b25、miR-212132、miR-183~182，以及上调的miR-335），它们以能够靶向一组特定的细胞调节因子和检查点传感器（包括Rb、E2F和Cdkns）而闻名，这些调节因子和传感器能够调节无Ras细胞中可逆改变的促增殖和抗增殖或应激反应途径之间的相互作用。 结论：我们的数据表明，无Ras细胞的可逆增殖表型是由一组特定的差异表达mRNA和microRNA构成的调节回路所调节的不同促增殖、抗增殖和应激反应途径之间相互作用的多效性结果，该调节回路优先靶向两个相互作用的信号轴：Myc-Rb-E2F依赖性途径和Cdkns-p53依赖性途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1627/4007593/f59005e04873/1471-2164-14-731-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1627/4007593/6e16b147fd53/1471-2164-14-731-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1627/4007593/ec12c78ea046/1471-2164-14-731-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1627/4007593/f1bc01ceaa5f/1471-2164-14-731-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1627/4007593/a5e9c9cc4af1/1471-2164-14-731-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1627/4007593/5b9fbb19f19a/1471-2164-14-731-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1627/4007593/f59005e04873/1471-2164-14-731-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1627/4007593/6e16b147fd53/1471-2164-14-731-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1627/4007593/ec12c78ea046/1471-2164-14-731-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1627/4007593/f1bc01ceaa5f/1471-2164-14-731-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1627/4007593/a5e9c9cc4af1/1471-2164-14-731-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1627/4007593/5b9fbb19f19a/1471-2164-14-731-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1627/4007593/f59005e04873/1471-2164-14-731-6.jpg

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[9]
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