Modulation of activity of the promoter of the human MDR1 gene by Ras and p53.
Drug resistance in human cancer is associated with overexpression of the multidrug resistance (MDR1) gene, which confers cross-resistance to hydrophobic natural product cytotoxic drugs. Expression of the MDR1 gene can occur de novo in human cancers in the absence of drug treatment. The promoter of the human MDR1 gene was shown to be a target for the c-Ha-Ras-1 oncogene and the p53 tumor suppressor gene products, both of which are associated with tumor progression. The stimulatory effect of c-Ha-Ras-1 was not specific for the MDR1 promoter alone, whereas a mutant p53 specifically stimulated the MDR1 promoter and wild-type p53 exerted specific repression. These results imply that the MDR1 gene could be activated during tumor progression associated with mutations in Ras and p53.
Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD 20892.
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Chin
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Ueda
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Pastan
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Gottesman
D016475:3T3 Cells; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D002460:Cell Line; D004351:Drug Resistance; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D011905:Genes, ras; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D011401:Promoter Regions, Genetic; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras)