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Regulation of c-Myc expression by nickel ions and hypoxia.

机译：镍离子和缺氧对c-Myc表达的调节。

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摘要

In this dissertation research project, nickel (Ni) ions were found to increase protein levels and activities of c-Myc in non-tumorigenic cells but decreased them in tumorigenic cells. In non-tumorigenic Beas-2B cells, Ni ions increased c-Myc mRNA levels and promoter activity without affecting its mRNA stability. In contrast, in tumorgeinic A549 cells, although Ni ions also induced c-Myc promoter activity, the mRNA level of c-Myc was slightly decreased by Ni ions through a reduction in c-Myc mRNA stability. However, Ni ions decreased c-Myc protein stability in both cell lines. Further studies showed that Ni ions induced c-Myc-dependent apoptosis in Beas-2B, but not in A549, cells. Moreover, an ERK pathway was involved in Ni ion-induced dysregulation of c-Myc in Beas-2B, but not in A549, cells. The hypoxia mimesis (deferoxamine [DFO] and dimethyloxyalylglycine [DMOG]), as well as hypoxia itself, each stabilized hypoxia-inducible factor (HIF)-2alpha and decreased c-Myc protein levels in both cell lines. The decrease in c-Myc protein levels in A549 cells was primarily due to proteasomal degradation mediated by PP2A and Fbw7 in a T58-phosphorylation-dependent manner. Both HIF-1alpha and HIF-2alpha were involved in this degradation in A549, but not in Beas-2B, cells. There were two scenarios that resulted in an increase in ubiquitinated-c-Myc levels (Ub-c-Myc) in A549 cells: the first involved an increased phosphorylation of c-Myc at T58 by an alternate kinase that was not GSK3beta; the second involved a decrease in USP28 protein levels partially mediated by HIF-1alpha and HIF-2alpha. Nickel ions and hypoxia increased the levels of dimethylated H3 lysine 9 at USP28 promoter region; this could contribute to the repression of USP28 gene expression induced by hypoxia. In addition, hypoxia decreased acetylation levels on histone H4 in both A549 and Beas-2B cells; this effect was dependent upon c-Myc. While this study revealed the differential effects of Ni ions on c-Myc regulation in non-tumorigenic and tumorigenic cells and the probable underlying mechanisms, it also provided evidence for a unique role of HIFs in c-Myc degradation in the A549 cancer cell line. These results implicate dysregulated c-Myc in Ni ion-induced carcinogenenesis.
机译：在本论文的研究项目中，发现镍（Ni）离子可增加非致瘤细胞中的蛋白质水平和c-Myc活性，但会降低致癌细胞中的c-Myc活性。在非致瘤的Beas-2B细胞中，Ni离子增加c-Myc mRNA水平和启动子活性，而不影响其mRNA稳定性。相反，在肿瘤基因产生的A549细胞中，尽管Ni离子也诱导c-Myc启动子活性，但是Ni离子通过降低c-Myc mRNA的稳定性而使c-Myc的mRNA水平略有下降。但是，镍离子降低了两种细胞系中c-Myc蛋白的稳定性。进一步的研究表明，Ni离子在Beas-2B细胞中诱导c-Myc依赖性凋亡，但在A549细胞中却不诱导。此外，ERK途径参与了Beas-2B中Ni离子诱导的c-Myc失调，但不参与A549细胞。缺氧模仿（去铁胺[DFO]和二甲基氧代甘氨酰甘氨酸[DMOG]）以及缺氧本身，均稳定了两种细胞系中的缺氧诱导因子（HIF）-2alpha并降低了c-Myc蛋白水平。 A549细胞中c-Myc蛋白水平的下降主要是由于PP2A和Fbw7以T58磷酸化依赖性方式介导的蛋白酶体降解。 HIF-1alpha和HIF-2alpha都参与了A549细胞的降解，但没有参与Beas-2B细胞的降解。有两种情况导致A549细胞中泛素化c-Myc水平（Ub-c-Myc）升高：第一种情况涉及T58处c-Myc磷酸化的替代激酶（不是GSK3beta）增加。第二个涉及部分由HIF-1alpha和HIF-2alpha介导的USP28蛋白水平的降低。镍离子和缺氧增加了USP28启动子区域的二甲基化H3赖氨酸9的水平；这可能有助于抑制缺氧诱导的USP28基因表达。此外，缺氧降低了A549和Beas-2B细胞中组蛋白H4的乙酰化水平。这种作用取决于c-Myc。尽管这项研究揭示了镍离子对非致瘤和致瘤细胞中c-Myc调控的不同作用以及可能的潜在机制，但它也提供了HIF在A549癌细胞系c-Myc降解中的独特作用的证据。这些结果暗示镍离子诱导的致癌作用中c-Myc失调。

著录项

  • 作者

    Li, Qin.;

  • 作者单位

    New York University.;

  • 授予单位 New York University.;
  • 学科 Biology Molecular.;Health Sciences Toxicology.;Environmental Sciences.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 174 p.
  • 总页数 174
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;环境科学基础理论;毒物学（毒理学）;
  • 关键词

  • 入库时间 2022-08-17 11:38:30

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