A novel exon within the mdm2 gene modulates translation initiation in vitro and disrupts the p53-binding domain of mdm2 protein.
The mdm2 protein interacts with a number of proteins involved in cell growth control. Such interactions favour cell proliferation and may explain the oncogenic potential of mdm2 when over-expressed in cells. Interaction with the tumour suppressor p53 involves the N-terminus of mdm2 and targets p53 for rapid degradation by the ubiquitin pathway. We now describe a novel, highly conserved exon of mdm2 (exon alpha) which includes an in-frame UGA stop codon. Expression of exon alpha disrupts in vitro translation of the p53 binding domain of mdm2. We propose that exon alpha induces translation re-initiation at an internal AUG codon within the mdm2 alpha mRNA isoform. The putative mdm2 alpha protein lacks the N-terminus of mdm2 and shows little, if any, binding capacity for p53. Mdm2 alpha mRNA is expressed in a tissue-specific manner and is observed predominantly in testis and peripheral blood lymphocytes. We propose that mdm2 alpha expression may provide a mechanism for uncoupling mdm2-p53 interaction in certain cell types and/or under specific conditions of cell growth.
Veldhoen
N
N
Department of Biology, University of York, UK.
Metcalfe
S
S
Milner
J
J
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003062:Codon; D017124:Conserved Sequence; D018076:DNA, Complementary; D004285:Dogs; D005091:Exons; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D013737:Testis / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D003062:Codon; D018076:DNA, Complementary; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2