Characterisation of a novel p53 down-regulated promoter in intron 3 of the human MDM2 oncogene.
The MDM2 oncogene exhibits a complex expression pattern partly due to the usage of multiple promoters. Two MDM2 promoters (P1 and P2) have been identified. P1 is located upstream of exon 1 and is modulated by PTEN. P2 sits in intron 1 and is activated by p53. Here we report the discovery of a third promoter (designated P3) in intron 3 of this gene, which contains a TATA-box element and p53-DNA-binding sequences. DNA-protein binding assays indicated that p53 bound to this region specifically. This region also demonstrated promoter activity in a reporter gene system, which was down-regulated by p53. Furthermore, experiments combining P2 and P3 in the same reporter construct indicated that P3 had a suppressive effect on P2 at high levels of p53. These results suggest that one of the P3 functions is to dampen the expression of MDM2 at high levels of p53, adding an additional element to the feedback loop between p53 and MDM2.
Liang
Huiling
H
Northern Institute for Cancer Research, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, NE2 4HH, UK.
Lunec
John
J
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D006801:Humans; D007438:Introns / Q000235:genetics*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D018411:Spodoptera; D016385:TATA Box / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D008156:Luciferases; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2