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Regulation of c-Myc expression by ni...

New York University., Environmental Health Science.

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

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Regulation of c-Myc expression by nickel ions and hypoxia./
作者:	Li, Qin.
面頁冊數:	174 p.
附註:	Adviser: Max Costa.
Contained By:	Dissertation Abstracts International70-01B.
標題:	Biology, Molecular. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3342396
ISBN:	9781109902402

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

Regulation of c-Myc expression by nickel ions and hypoxia. - 174 p.

Adviser: Max Costa.

Thesis (Ph.D.)--New York University, 2009.

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.

ISBN: 9781109902402Subjects--Topical Terms:

1017719
Biology, Molecular.

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