Hdmx recruitment into the nucleus by Hdm2 is essential for its ability to regulate p53 stability and transactivation.
The Hdmx gene product is related to the Hdm2 oncoprotein, both of which interact with and regulate p53 stability and function. Like Hdm2, Hdmx is able to inhibit p53 transactivation; however, at variance with Hdm2, which promotes ubiquitination, nuclear export, and degradation of p53, Hdmx increases p53 stability. We report here (i) that overexpressed Hdmx is cytoplasmic and Hdm2 recruits Hdmx into the nucleus and (ii) that nuclear Hdmx blocks Hdm2-mediated nuclear export of p53 and down-regulates p53-dependent transcription. Furthermore we showed that Hdmx inhibits Hdm2-mediated p53 ubiquitination. It appears, therefore, that a regulatory loop exists in which Hdm2 regulates the intracellular localization of Hdmx, and nuclear Hdmx regulates several functions of Hdm2 (ubiquitin ligase activity and p53 nuclear export).
Migliorini
Domenico
D
Department of Experimental Oncology, European Institute of Oncology, 435 Via Ripamonti, 20141 Milan, Italy.
Danovi
Davide
D
Colombo
Emanuela
E
Carbone
Roberta
R
Pelicci
Pier Giuseppe
PG
Marine
Jean-Christophe
JC
D016475:3T3 Cells; D021581:Active Transport, Cell Nucleus; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D019084:Fluorescent Antibody Technique, Indirect; D016158:Genes, p53 / Q000235:genetics; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism
D008164:Luminescent Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2