Genome-wide functional analysis of human cell-cycle regulators
Genome-wide functional analysis of human cell-cycle regulators
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DOI：
10.1073/pnas.0604320103
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发表时间：
2006-10-03
影响因子：
11.1
通讯作者：
Schultz, Peter G.
中科院分区：
文献类型：
--
作者：
Mukherji, Mridul;Bell, Russell;Schultz, Peter G.
人类细胞已经进化出复杂的信号网络来协调细胞周期。要详细了解这一基本过程的全局调控，需要全面鉴定细胞周期进程各个阶段所涉及的基因和途径。为此，我们报告了人类细胞周期，细胞大小和增殖的全基因组分析，通过使用小干扰RNA（siRNA）靶向人类基因组中> 95%的蛋白质编码基因。通过定量荧光显微镜获得的超过200万张图像的分析表明，1，152个基因的缺失强烈影响细胞周期进程。这些基因聚类成八个不同的表型类别的基础上逮捕，核面积和核形态。通过查询具有识别基因的基于知识的和物理相互作用的数据库来构建阶段特异性网络。对细胞周期调节因子的全基因组分析揭示了许多激酶、磷酸酶和蛋白水解蛋白，并且还表明被认为调节Gi-S期进展的过程（如受体介导的信号传导、营养状态和翻译）也在调节中发挥重要作用G（2）/M相转变。此外，15个基因是TNF/NF-κ B信号传导的组成部分，被发现调节G（2）/M，这是以前没有预料到的作用，这一途径。这些分析提供了对已知和新基因以及调节细胞周期进程的途径的系统水平的洞察，其中一些可能为癌症的治疗提供新的治疗方法。
Human cells have evolved complex signaling networks to coordinate the cell cycle. A detailed understanding of the global regulation of this fundamental process requires comprehensive identification of the genes and pathways involved in the various stages of cell-cycle progression. To this end, we report a genome-wide analysis of the human cell cycle, cell size, and proliferation by targeting > 95% of the protein-coding genes in the human genome using small interfering RNAs (siRNAs). Analysis of > 2 million images, acquired by quantitative fluorescence microscopy, showed that depletion of 1,152 genes strongly affected cell-cycle progression. These genes clustered into eight distinct phenotypic categories based on phase of arrest, nuclear area, and nuclear morphology. Phase-specific networks were built by interrogating knowledge-based and physical interaction databases with identified genes. Genome-wide analysis of cell-cycle regulators revealed a number of kinase, phosphatase, and proteolytic proteins and also suggests that processes thought to regulate Gi-S phase progression like receptor-mediated signaling, nutrient status, and translation also play important roles in the regulation of G(2)/M phase transition. Moreover, 15 genes that are integral to TNF/NF-kappa B signaling were found to regulate G(2)/M, a previously unanticipated role for this pathway. These analyses provide systems-level insight into both known and novel genes as well as pathways that regulate cell-cycle progression, a number of which may provide new therapeutic approaches for the treatment of cancer.