The Mdm Network and Its Regulation of p53 Activities: A Rheostat of Cancer Risk

• Published in: Human mutation Vol. 35; no. 6; pp. 728 - 737
• Main Authors: Eischen, Christine M., Lozano, Guillermina
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01-06-2014; Hindawi Limited
• Subjects: Animals; Cell Cycle Checkpoints - genetics; Cell Death - genetics; Cell Proliferation - genetics; Humans; Mdm2; Mdm4; Medical research; Mice; mouse models; Neoplasms - genetics; Neoplasms - pathology; Nuclear Proteins - genetics; p53; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-mdm2 - genetics; Risk Factors; TCGA; TP53; Transcription, Genetic; Trp53; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - genetics; Tumors; mouse models; Trp53; Mdm2; Mdm4; TP53; TCGA; p53
• ISSN: 1059-7794; 1098-1004
• DOI: 10.1002/humu.22524

ABSTRACT
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.