The region 3' to the major transcriptional start site of the MDR1 downstream promoter mediates activation by a subset of mutant P53 proteins.
We have examined the response of the human multidrug resistance gene-1 (MDR1) downstream promoter to various mutants of human p53 in a reporter assay system. Our findings indicate that mutant 175H inhibits reporter activity driven by the MDR1 downstream promoter (base pairs -189 to +133 relative to the major transcriptional initiation site) in a dose-dependent manner in cotransfection assays in the BHK and the Saos-2 cell lines. A 123 base-pair segment of DNA (-119 to +4 relative to the major transcriptional initiation site) and a 193 base-pair segment (-189 to +4) have been isolated from the MDR1 downstream promoter which, like the full promoter, are negatively controlled by mutant 175H. However, a 135 base-pair segment (-2 to +133) of the promoter is activated by mutant 175H as well as mutant 248Q, but not by mutants 213Q and 234H. Thus some mutants of p53 are able to activate transcription from the 3' region of the MDR1 downstream promoter, an activity that characterizes these p53 mutants as "gain of function" mutants.
Department of Pathology, University of California, San Diego, La Jolla, USA.
B E
BE
Strauss
M
M
Haas
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D006224:Cricetinae; D017931:DNA Primers / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics*; D017930:Genes, Reporter; D016158:Genes, p53; D005822:Genetic Vectors; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D017931:DNA Primers; D016159:Tumor Suppressor Protein p53; D008156:Luciferases