Global regulation of nucleotide biosynthetic genes by c-Myc.
Global regulation of nucleotide biosynthetic genes by c-Myc.
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DOI：
10.1371/journal.pone.0002722
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发表时间：
2008-07-16
期刊：
影响因子：
3.7
通讯作者：
Dang CV
中科院分区：
文献类型：
--
作者：
Liu YC;Li F;Handler J;Huang CR;Xiang Y;Neretti N;Sedivy JM;Zeller KI;Dang CV
c-Myc转录因子是一个主要的调节因子，通过激活数千个靶基因来整合细胞增殖、细胞生长和代谢。我们通过染色质免疫沉淀（ChIP）结合双端双标签测序分析（ChIP-PET）对c-Myc直接靶基因的鉴定表明，核苷酸代谢基因在c-Myc靶基因中富集，但Myc在调节核苷酸代谢基因中的作用尚未得到全面描述。在此，我们报告了在人Burkitt淋巴瘤模型细胞系P493-6中，人嘌呤和嘧啶生物合成途径中的大多数基因被c-Myc诱导并直接结合。这些基因中的大多数也响应于配体激活的Myc-雌激素受体融合蛋白，Myc-ER，在Myc空大鼠成纤维细胞系，HO.15 MYC-ER。此外，这些靶标也对体内转基因小鼠肝脏中的Myc活化有响应。为了确定c-Myc调节核苷酸代谢的功能意义，我们试图确定直接Myc靶向肌苷单磷酸脱氢酶（IMPDH 1和IMPDH 2）的功能丧失对c-Myc诱导的细胞生长和增殖的影响。在这方面，我们使用了一个特定的IMPDH抑制剂霉酚酸（MPA），并发现MPA显着抑制c-Myc诱导的P493-6细胞增殖，通过S期阻滞和凋亡。综上所述，这些结果证明了在多个系统中c-Myc对核苷酸代谢基因的直接诱导。我们在IMPDH活性降低的细胞中发现S期阻滞，这表明核苷酸库平衡对于c-Myc的DNA复制协调是必不可少的，使得这两个过程的解偶联产生DNA复制应激和凋亡。
The c-Myc transcription factor is a master regulator and integrates cell proliferation, cell growth and metabolism through activating thousands of target genes. Our identification of direct c-Myc target genes by chromatin immunoprecipitation (ChIP) coupled with pair-end ditag sequencing analysis (ChIP-PET) revealed that nucleotide metabolic genes are enriched among c-Myc targets, but the role of Myc in regulating nucleotide metabolic genes has not been comprehensively delineated. Here, we report that the majority of genes in human purine and pyrimidine biosynthesis pathway were induced and directly bound by c-Myc in the P493-6 human Burkitt's lymphoma model cell line. The majority of these genes were also responsive to the ligand-activated Myc-estrogen receptor fusion protein, Myc-ER, in a Myc null rat fibroblast cell line, HO.15 MYC-ER. Furthermore, these targets are also responsive to Myc activation in transgenic mouse livers in vivo. To determine the functional significance of c-Myc regulation of nucleotide metabolism, we sought to determine the effect of loss of function of direct Myc targets inosine monophosphate dehydrogenases (IMPDH1 and IMPDH2) on c-Myc-induced cell growth and proliferation. In this regard, we used a specific IMPDH inhibitor mycophenolic acid (MPA) and found that MPA dramatically inhibits c-Myc-induced P493-6 cell proliferation through S-phase arrest and apoptosis. Taken together, these results demonstrate the direct induction of nucleotide metabolic genes by c-Myc in multiple systems. Our finding of an S-phase arrest in cells with diminished IMPDH activity suggests that nucleotide pool balance is essential for c-Myc's orchestration of DNA replication, such that uncoupling of these two processes create DNA replication stress and apoptosis.
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影响因子：
5.3
作者：
de Marval, PLM;Macias, E;Rodriguez-Puebla, ML
通讯作者：
Rodriguez-Puebla, ML
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8
作者：
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10.5
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作者：
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通讯作者：
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4.8
作者：
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通讯作者：
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