The human MDM2 oncoprotein increases the transcriptional activity and the protein level of the p53 homolog p63.
Genetic alteration of the p53 tumor suppressor gene, which monitors DNA damage and operates cell cycle checkpoints, is a major factor in the development of human malignancies. The p53 protein belongs to a family that also includes two structurally related proteins, p63 and p73. Although all three proteins share similar transcriptional functions and antiproliferative effects, each of them appears to play a distinct role in development and tumor suppression. One of the principal regulators of p53 activity is the MDM2 protein. The interaction of MDM2 with p53 inhibits p53 transcriptional activity and targets p53 for ubiquitin-dependent degradation. The ability of MDM2 to inhibit p53 functions is antagonized by the ARF oncosuppressor protein. We show here that like p53, the p63alpha and p63gamma isoforms are able to associate with human MDM2 (HDM2). Overexpression of HDM2 increased the steady-state level of intracellular p63 and enhanced its transcriptional activity. Both effects appeared to be counteracted by ARF coexpression. These data indicate that p63 can be activated by HDM2 under conditions in which p53 is inhibited. Therefore, HDM2 expression could support p63-specific transcriptional functions on a common set of genes, keeping interference by p53 at a minimum.
Calabrò
Viola
V
Department of Genetics and General and Molecular Biology, University of Naples "Federico II," via Mezzocannone 8, 80134 Napoli, Italy.
Mansueto
Gelsomina
G
Parisi
Tiziana
T
Vivo
Maria
M
Calogero
Raffaele A
RA
La Mantia
Girolama
G
D000818:Animals; D019556:COS Cells; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins; D009687:Nuclear Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000737:chemistry*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015534:Trans-Activators / Q000096:biosynthesis* / Q000737:chemistry*; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin / Q000378:metabolism
C081876:CKAP4 protein, human; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; C115051:TP63 protein, human; C000606460:TP73 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D005982:Glutathione Transferase