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

    Author(s)
    Amalraj, James
    Cutler, Samuel J
    Ghazawi, Ibtisam
    Boyle, Glen M
    Ralph, Stephen J
    Griffith University Author(s)
    Ghazawi, Ibtisam
    Ralph, Stephen J.
    Cutler, Samuel J.
    Amalraj, James
    Year published
    2013
    Metadata
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    Abstract
    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-a/߭induced complex, ISGF3. Together with the previously ...
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    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-a/߭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.
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    Journal Title
    Molecular Cancer Therapeutics
    Volume
    12
    Issue
    7
    DOI
    https://doi.org/10.1158/1535-7163.MCT-12-0923
    Subject
    Oncology and Carcinogenesis not elsewhere classified
    Pharmacology and Pharmaceutical Sciences not elsewhere classified
    Oncology and Carcinogenesis
    Pharmacology and Pharmaceutical Sciences
    Publication URI
    http://hdl.handle.net/10072/61345
    Collection
    • Journal articles

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