Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion
Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion
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DOI：
10.1073/pnas.97.7.3260
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发表时间：
2000-03-28
影响因子：
11.1
通讯作者：
Golub, TR
中科院分区：
文献类型：
--
作者：
Coller, HA;Grandori, C;Golub, TR
MYC通过改变基因表达影响正常和肿瘤细胞增殖，但确切的途径仍不清楚。我们使用寡核苷酸微阵列分析了6，416个基因和表达的序列标签，以确定原代人成纤维细胞中c-MYC激活引起的基因表达变化。在这些实验中，27个基因被一致诱导，9个基因被抑制。这些基因的身份揭示了MYC可能影响转化细胞中改变的细胞生理学的许多方面：细胞生长、细胞周期、粘附和细胞骨架组织。已鉴定的可能与MYC对细胞生长的影响有关的靶点包括核仁蛋白核仁素和原纤蛋白，以及真核起始因子5A。在确定为目标的细胞周期基因中，G1期细胞周期蛋白D2和细胞周期蛋白依赖性激酶结合蛋白CksHs 2被诱导，而细胞周期蛋白依赖性激酶抑制剂p21（Cip 1）被抑制。MYC在调节细胞粘附和结构中的作用是通过抑制编码细胞外基质蛋白纤连蛋白和胶原蛋白以及细胞骨架蛋白原肌球蛋白的基因来提出的。通过鉴定肿瘤坏死因子受体相关蛋白TRAP 1作为MYC靶点，揭示了MYC介导的细胞凋亡的可能机制。最后，两个immunophilins，肽基脯氨酰顺反异构酶F和FKBP 52，其中后者在拟南芥细胞分裂中起作用，上调MYC我们还探讨了模式匹配方法作为一种替代方法来确定MYC靶基因。在骨髓分化模型的基于微阵列的表达谱中显示与内源性Myc最相似的表达谱的基因高度富集MYC靶基因。
MYC affects normal and neoplastic cell proliferation by altering gene expression, but the precise pathways remain unclear. We used oligonucleotide microarray analysis of 6,416 genes and expressed sequence tags to determine changes in gene expression caused by activation of c-MYC in primary human fibroblasts. In these experiments, 27 genes were consistently induced, and 9 genes were repressed. The identity of the genes revealed that MYC may affect many aspects of cell physiology altered in transformed cells: cell growth, cell cycle, adhesion, and cytoskeletal organization. Identified targets possibly linked to MYC's effects on cell growth include the nucleolar proteins nucleolin and fibrillarin, as well as the eukaryotic initiation factor 5A. Among the cell cycle genes identified as targets, the G1 cyclin D2 and the cyclin-dependent kinase binding protein CksHs2 were induced whereas the cyclin-dependent kinase inhibitor p21(Cip1) was repressed. A role for MYC in regulating cell adhesion and structure is suggested by repression of genes encoding the extracellular matrix proteins fibronectin and collagen, and the cytoskeletal protein tropomyosin. A possible mechanism far MYC-mediated apoptosis was revealed by identification of the tumor necrosis factor receptor associated protein TRAP1 as a MYC target. Finally, two immunophilins, peptidyl-prolyl cis-trans isomerase F and FKBP52, the latter of which plays a role in cell division in Arabidopsis, were up-regulated by MYC We also explored pattern-matching methods as an alternative approach for identifying MYC target genes. The genes that displayed an expression profile most similar to endogenous Myc in microarray-based expression profiling of myeloid differentiation models were highly enriched for MYC target genes.