The mechanism of trans-activation of the MDR1 gene by human T-cell leukemia virus.
Overexpression of P-glycoprotein (P-gp), the protein product of the multidrug resistance gene (MDR1), confers a drug resistant phenotype on cells. We have recently demonstrated that the MDR1 promoter is transcriptionally activated by the HTLV-I tax protein, providing an explanation for the development of drug resistance in HTLV-I infections. Here we report that HTLV-I mediated MDR1 activation is dependent on the presence of an NF-IL6-binding site located between base pairs -148 and -141 relative to the transcription start site. This finding opens up the possibility of moderating P-gp expression through interference with NF-IL6 binding to its trans recognition element and subsequent repression of MDR1 transcription.
Wellcome/CRC Institute, Tennis Court Road, Cambridge, CB2 1QR, United Kingdom.
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D033965:Adaptor Protein Complex alpha Subunits; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001665:Binding Sites; D022762:CCAAT-Enhancer-Binding Proteins; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000378:metabolism; D017353:Gene Deletion; D015870:Gene Expression; D016356:Gene Products, tax / Q000494:pharmacology*; D019450:Genes, MDR / Q000235:genetics*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D033965:Adaptor Protein Complex alpha Subunits; D033942:Adaptor Proteins, Vesicular Transport; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D016356:Gene Products, tax; D008565:Membrane Proteins; D009687:Nuclear Proteins