Transcriptional regulation of the human MDR1 gene at the level of the inverted MED-1 promoter region.

Abstract

The typical multidrug resistance phenotype (MDR), the major cause of failure of cancer chemotherapy, is the result of the overexpression of the human MDR1 gene, the regulation of which is still incompletely understood. Using several EMSA experiments, we have identified a new regulatory sequence located from -103 to -98 bp relative to the +1 start site in the MDR1 promoter region. This sequence, which we called inverted MED-1, acts as a cis-activator for this gene. In transient transfection experiments of highly resistant human lymphoblastic CEM/VLB5 cells, its deletion from the promoter region is responsible for 60% inhibition of the MDR1 transcriptional activity. This sequence specifically binds a nuclear protein of about 150-160 kDa. We showed that its binding capacity is related to the chemoresistance level of the studied cell lines and may reflect the increased transcriptional activity of the MDR1 gene in multidrug-resistant cells.