REST Negatively and ISGF3 Positively Regulate the Human STAT1 Gene in Melanoma

被引:9
|
作者
Amalraj, James [1 ,2 ]
Cutler, Samuel J. [1 ,2 ]
Ghazawi, Ibtisam [1 ,2 ]
Boyle, Glen M. [3 ]
Ralph, Stephen J. [1 ,2 ]
机构
[1] Griffith Univ, Sch Med Sci, Nathan, Qld 4111, Australia
[2] Griffith Univ, Genom Res Ctr, Griffith Hlth Inst, Nathan, Qld 4111, Australia
[3] Queensland Inst Med Res, Ctr Drug Discovery, Herston, Qld 4006, Australia
关键词
RESTRICTIVE SILENCER FACTOR; SIGNAL-TRANSDUCTION PATHWAY; MALIGNANT-MELANOMA; INTERFERON-ALPHA; FACTOR FAMILY; TARGET GENES; CELL-LINES; IFN-GAMMA; EXPRESSION; REPRESSOR;
D O I
10.1158/1535-7163.MCT-12-0923
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
STAT1 plays a pivotal role in signal transduction and transcriptional activation in response to type I and II IFNs. Regulation of STAT1 expression has significant consequences in human cancer cells, where STAT1 deficiencies have been associated with cellular resistance to type I IFN. Distinct promoter, enhancer, and repressor regions have previously been described in the regulatory part of the human STAT1 gene extending as far as the second intron. A putative IFN-stimulated response element sequence in the STAT1 promoter is inducible by type I IFN and binds the IFN-alpha/beta-induced complex, ISGF3. Together with the previously characterized IRF-E/GAS/IRF-E (IGI) motif, these positive regulatory elements provide a means for intracellular amplification of STAT1 expression, which is necessary for increasing cell responsiveness to the IFNs. In contrast, the transcriptional repressor REST binds to an RE-1 element in the STAT1 repressor region and in doing so represses transcription from the STAT1 gene regulatory region in melanoma cells lines. Repression significantly decreased in a REST-null cell line. Altering REST function from a transcriptional repressor into an activator as REST-VP16 increased expression from RE-1-targeted reporters. RNA expression of 65 melanoma cell lines by microarray and selected lines with known IFN responsiveness showed significant inverse correlations between STAT1/REST that were related to cellular responses to IFN. Thus REST, through the intronic RE-1 element, provides a means for downregulating STAT1 expression, affecting melanoma responsiveness to IFN. Intracellular levels of REST may be a useful marker to test for IFN resistance and as a novel therapeutic target in IFN-resistant melanomas. (C) 2013 AACR.
引用
收藏
页码:1288 / 1298
页数:11
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