사람 다제내성유전자 상부 promotor의 활성도
(The) Upstream promotor activity of human MDR1 gene
MDR1 Promotor Alternative transcript 다제내성유전자 항암치료 종양세포;
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Background. Development of drug resistance is a major obstacle in cancer chemotherapy Cells have the general capacity to develop resistance to cytotoxic chemotherapy by various ways. One mechanism that has been found frequently is the overexpression of MDR1/Pgp. In many drug-resistant lymphoma cells, alternative transcripts with different non-coding 5' exon of MDR1 have been identified suggesting that the putative upstream promotor of MDR1 is responsible for the transcriptional regulation of the MDR1 gene after drug exposure. Until now most of all the study about the promotor of MDR1 is confined to main promoter of MDR1 and upstream promotor of MDR1 is not identified yet. Methods. In order to identify the putative upstream promotor that control alternative transcription, 5'-UTR proximal to alternative exon -1 of MDR1 was cloned by the method of Genome Walking and searched for its similar sequence at the Gene bank of TFSEARCH. The promotor activity was measured by luciferase activity after transfection of the promotor region into CHO cells. Results. Transcription start site controlled by putative upstream promotor exists 112kb upstream from exon 1 of MDR1. Gene Bank search showed that the putative upstream promotor region is within the 5^(th) intron of the LOC154661 gene encoding an unnamed protein (Model protein=XP_088000) which locates on centromeric to MDR1 gene on chromosome 7. However this gene is encoded on the antisense strand of the DNA while the MDR1 exons are encoded on the sense strand. The putative upstream promotor region showed bidirectional promotor activity and has characteristics of promotor region such as CAAT box, and numerous transcription factor binding motifs. The promotor activity in the reverse orientation is more potent than that in the orientation of MDR1 transcription. The expression of LOC154661 gene was widespread, suggesting that this may be a housekeeping gene. Conclusions. These results suggest that the putative upstream promotor of MDR1 is a gene regulatory element of neighboring gene which has bidirectional promotor activity. This suggest that the promotors or other gene regulatory sequences of house keeping genes can prime transcripts bi-directionally, Further study is warranted to explore how this aberrancy could be exaggerated with drug selection.