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• W2340582374 abstract "Multidrug resistance (MDR) is a major limitation in the successful treatment of cancerusing chemotherapy. Cancers can be intrinsically resistant or develop resistance duringtreatment to a variety of structurally and functional unrelated drugs. Numerous cellularmechanisms which contribute to MDR have been identified, however, the most commonmechanism is the over expression of a 170kDa glycoprotein referred to as P-glycoprotein(P-gp). P-gp acts as an ATP-dependant drug efflux pump and is encoded by the MDRI gene.An understanding of the regulation of the MDRI gene is essential if the clinical impact ofMDR is to be reduced. However, at this stage how this gene is regulated in vivo remainselusive. Amplification of the MDRI gene or an increase in mRNA stability may increaseexpression in cells already expressing P-gp, though they do not account for activationand/or regulation of the MDRI gene itself. Hence the focus of many studies is on theregulation of MDRI transcription.The current study investigated the role of intron 1 in MDRI promoter regulation. The intron1 region has been shown to contain a CpG island which is differentially methylated in thedrug sensitive HL60 cells and completely unmethylated in MDR H/E8 cells. In vitroDNA:protein interactions were found to exist within this differentially methylated region.Thus the aim of the current study was to determine the functional role of the downstreamCpG island in MDRI regulation in cells of varying origin and varying MDR levels. TheMDR cells lines studied were the HL60 derived HlE8 leukaemic cell line, the K562 derivedKepru leukaemic cell line, the KB-3-J derived KB-8-5 cervical cancer cell lines and theLo Vo and L/ ADR colon cancer cell lines. Reporter gene studies indicated an overallnegative role in reporter activity for the +283 to +606bp region in the leukaemic MDR celllines, whilst the same region was shown to increase reporter activity in the KB-8-5 cells.The colon LoVo and L/ADR cells also showed an increase in activity for the +283 to+606bp, however, the increase was not found to be significant. Further subdivision of the+283 to +606bp region suggested the existence of several different potential and repressorand enhancer regulatory elements in the H/E8, Kepru and KB-8-5 MDR cell lines.Similarly, reporter gene functional studies of the +65 to +282bp region resulted in anoverall inhibitory effect in reporter gene activity in the HlE8 cells and a stimulatory effectin the KB-8-5, LoVo and L/ADR MDR cell lines. Further subdivision of the +65 to +282bpregion revealed several different potential repressor and enhancer elements in the cell linestested . This region had not been previously investigated for DNA:protein interactions.UV in vivo footprinting was used to investigate in vivo chromatin structure and potentialDNA:protein interactions in intron 1 of the MDRI gene. Sites of hypersensitivity andprotection were found in intron 1 in all cell lines, however, it is hypothesised that some ofthe…" @default.
• W2340582374 created "2016-06-24" @default.
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• W2340582374 date "2009-01-01" @default.
• W2340582374 modified "2023-09-23" @default.
• W2340582374 title "The role of intron 1 in MDR1 regulation in drug resistant cancer cells" @default.
• W2340582374 hasPublicationYear "2009" @default.
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