title: p53 Stability and activity is regulated by Mdm2-mediated induction of alternative p53 translation products.
abstract: Activation of the p53 tumour suppressor protein can lead to cell-cycle arrest or apoptosis. p53 function is controlled by the mdm2 oncogene product, which targets p53 for proteasomal degradation. In this report we demonstrate that Mdm2 induces translation of the p53 mRNA from two alternative initiation sites, giving full-length p53 and another protein with a relative molecular mass (M(r)) of approximately 47K; we designate this protein as p53/47. This translation induction requires Mdm2 to interact directly with the nascent p53 polypeptide. The alternatively translated p53/47 does not contain the Mdm2-binding site and it lacks the most amino-terminal transcriptional-activation domain of p53. Increased expression of p53/47 stabilizes p53 in the presence of Mdm2, and alters the expression levels of p53-induced gene products. These results show how the interaction of Mdm2 with p53 leads to a change in the ratio of full-length p53 to p53/47 by inducing translation of both p53 proteins and the subsequent selective degradation of full-length p53. Thus, Mdm2 controls the expression levels of p53 through a dual mechanism that involves induction of synthesis and targeting for degradation.
authors.affiliation: Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK.
authors.forename: Yili
authors.initials: Y
authors.lastname: Yin
authors.forename: C W
authors.initials: CW
authors.lastname: Stephen
authors.forename: M Gloria
authors.initials: MG
authors.lastname: Luciani
authors.forename: Robin
authors.initials: R
authors.lastname: Fåhraeus
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms; D018387:Codon, Initiator / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008175:Lung Neoplasms; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D014176:Protein Biosynthesis / Q000502:physiology*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D012341:RNA, Ribosomal, 5S / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018387:Codon, Initiator; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012341:RNA, Ribosomal, 5S; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2