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MDM2, MDMX, and p73 regulate cell-cycle progression in the absence of wild-type p53
- Source :
- Proc Natl Acad Sci U S A
- Publication Year :
- 2021
- Publisher :
- Proceedings of the National Academy of Sciences, 2021.
-
Abstract
- The p53 tumor suppressor protein, known to be critically important in several processes including cell-cycle arrest and apoptosis, is highly regulated by multiple mechanisms, most certifiably the Murine Double Minute 2–Murine Double Minute X (MDM2–MDMX) heterodimer. The role of MDM2–MDMX in cell-cycle regulation through inhibition of p53 has been well established. Here we report that in cells either lacking p53 or expressing certain tumor-derived mutant forms of p53, loss of endogenous MDM2 or MDMX, or inhibition of E3 ligase activity of the heterocomplex, causes cell-cycle arrest. This arrest is correlated with a reduction in E2F1, E2F3, and p73 levels. Remarkably, direct ablation of endogenous p73 produces a similar effect on the cell cycle and the expression of certain E2F family members at both protein and messenger RNA levels. These data suggest that MDM2 and MDMX, working at least in part as a heterocomplex, may play a p53-independent role in maintaining cell-cycle progression by promoting the activity of E2F family members as well as p73, making them a potential target of interest in cancers lacking wild-type p53.
- Subjects :
- MDMX
Ubiquitin-Protein Ligases
Apoptosis
Cell Cycle Proteins
Endogeny
Cell Line, Tumor
Proto-Oncogene Proteins
Animals
Humans
E2F1
Messenger RNA
Multidisciplinary
biology
Tumor Suppressor Proteins
Cell Cycle
Ubiquitination
Wild type
Nuclear Proteins
Proto-Oncogene Proteins c-mdm2
Tumor Protein p73
Cell Cycle Checkpoints
Biological Sciences
Cell cycle
Ubiquitin ligase
Cell biology
DNA-Binding Proteins
biology.protein
Mdm2
Tumor Suppressor Protein p53
E2F1 Transcription Factor
Protein Binding
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 118
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....c81dd6c6028f2aadf26783a02f56a683