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dc.contributor.authorAmalraj, James
dc.contributor.authorCutler, Samuel J
dc.contributor.authorGhazawi, Ibtisam
dc.contributor.authorBoyle, Glen M
dc.contributor.authorRalph, Stephen J
dc.description.abstractSTAT1 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.
dc.publisherAmerican Association for Cancer Research
dc.publisher.placeUnited States
dc.relation.ispartofjournalMolecular Cancer Therapeutics
dc.subject.fieldofresearchOncology and Carcinogenesis not elsewhere classified
dc.subject.fieldofresearchPharmacology and Pharmaceutical Sciences not elsewhere classified
dc.subject.fieldofresearchOncology and Carcinogenesis
dc.subject.fieldofresearchPharmacology and Pharmaceutical Sciences
dc.titleREST Negatively and ISGF3 Positively Regulate the Human STAT1 Gene in Melanoma
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
gro.facultyGriffith Health, School of Medical Science
gro.hasfulltextNo Full Text
gro.griffith.authorGhazawi, Ibtisam
gro.griffith.authorRalph, Stephen J.
gro.griffith.authorCutler, Samuel J.
gro.griffith.authorAmalraj, James

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