Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2.
The stability of the p53 tumor suppressor protein is critically regulated by the Hdm2 and Hdmx proteins. Hdm2 protein levels are auto-regulated by the self-ubiquitination activity of Hdm2 and on the transcriptional level by p53-activated transcription of the hdm2 gene. Little is known about the regulation of Hdmx expression levels, apart from the observation that the Mdmx protein can be cleaved by caspase-3 in a p53-inducible manner. In the functional analysis of two mutant Hdmx proteins, products of two alternatively spliced mRNAs, it was found that Hdmx proteins are targets for ubiquitination by Mdm2. The stability of the Hdmx protein is partly dependent on the presence of its internal acidic domain. Mdm2 appears only to require an intact RING domain to be able to ubiquitinate Hdmx and target it for proteasomal degradation. These findings highlight the intricate functional relationships between p53, Mdm2, and Hdmx.
de Graaf
Petra
P
Leiden University Medical Center, Department of Molecular and Cell Biology and Center for Biomedical Genetics, P. O. Box 9503, 2300 RA Leiden, The Netherlands.
Little
Natalie A
NA
Ramos
Yolande F M
YF
Meulmeester
Erik
E
Letteboer
Stef J F
SJ
Jochemsen
Aart G
AG
D017398:Alternative Splicing; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D003513:Cycloheximide / Q000494:pharmacology; D005091:Exons; D005822:Genetic Vectors; D006801:Humans; D007763:Lac Operon; D008025:Ligases / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009687:Nuclear Proteins; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D009687:Nuclear Proteins; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; D012313:RNA; D003513:Cycloheximide; D008156:Luciferases; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D008025:Ligases