dc.contributor.author | Amalraj, James | |
dc.contributor.author | Cutler, Samuel J | |
dc.contributor.author | Ghazawi, Ibtisam | |
dc.contributor.author | Boyle, Glen M | |
dc.contributor.author | Ralph, Stephen J | |
dc.date.accessioned | 2017-05-03T13:13:42Z | |
dc.date.available | 2017-05-03T13:13:42Z | |
dc.date.issued | 2013 | |
dc.date.modified | 2014-07-14T05:57:01Z | |
dc.identifier.issn | 1535-7163 | |
dc.identifier.doi | 10.1158/1535-7163.MCT-12-0923 | |
dc.identifier.uri | http://hdl.handle.net/10072/61345 | |
dc.description.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 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.description.peerreviewed | Yes | |
dc.description.publicationstatus | Yes | |
dc.language | English | |
dc.language.iso | eng | |
dc.publisher | American Association for Cancer Research | |
dc.publisher.place | United States | |
dc.relation.ispartofstudentpublication | N | |
dc.relation.ispartofpagefrom | 1288 | |
dc.relation.ispartofpageto | 1298 | |
dc.relation.ispartofissue | 7 | |
dc.relation.ispartofjournal | Molecular Cancer Therapeutics | |
dc.relation.ispartofvolume | 12 | |
dc.rights.retention | Y | |
dc.subject.fieldofresearch | Oncology and carcinogenesis | |
dc.subject.fieldofresearch | Oncology and carcinogenesis not elsewhere classified | |
dc.subject.fieldofresearch | Pharmacology and pharmaceutical sciences | |
dc.subject.fieldofresearch | Pharmacology and pharmaceutical sciences not elsewhere classified | |
dc.subject.fieldofresearchcode | 3211 | |
dc.subject.fieldofresearchcode | 321199 | |
dc.subject.fieldofresearchcode | 3214 | |
dc.subject.fieldofresearchcode | 321499 | |
dc.title | REST Negatively and ISGF3 Positively Regulate the Human STAT1 Gene in Melanoma | |
dc.type | Journal article | |
dc.type.description | C1 - Articles | |
dc.type.code | C - Journal Articles | |
gro.faculty | Griffith Health, School of Medical Science | |
gro.hasfulltext | No Full Text | |
gro.griffith.author | Ralph, Stephen J. | |