The Mdm network and its regulation of p53 activities: a rheostat of cancer risk.
The potent transcriptional activity of p53 (Trp53, TP53) must be kept in check for normal cell growth and survival. Tumors, which drastically deviate from these parameters, have evolved multiple mechanisms to inactivate TP53, the most prevalent of which is the emergence of TP53 missense mutations, some of which have gain-of-function activities. Another important mechanism by which tumors bypass TP53 functions is via increased levels of two TP53 inhibitors, MDM2, and MDM4. Studies in humans and in mice reveal the complexity of TP53 regulation and the exquisite sensitivity of this pathway to small changes in regulation. Here, we summarize the factors that impinge on TP53 activity and thus cell death/arrest or tumor development.
Vanderbilt University Medical Center, Department of Pathology, Microbiology and Immunology, Nashville, Tennessee.
Christine M
CM
Eischen
Guillermina
G
Lozano
D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics; D018797:Cell Cycle Proteins; D016923:Cell Death / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D012307:Risk Factors; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics*
D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
Mdm2; Mdm4; TCGA; TP53; Trp53; mouse models; p53