ArticleMolecular and cellular biology2002
Hypophosphorylation of Mdm2 augments p53 stability.
Article in Molecular and cellular biology, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed, 144 citations in OpenAlex.
- Endocytic Control of Cell-Autonomous and Non-Cell-Autonomous Functions of p53.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Circadian gene CSNK1D promoted the progression of hepatocellular carcinoma by activating Wnt/β-catenin pathway via stabilizing Dishevelled Segment Polarity Protein 3.Biological procedures online · 2022Article
- Targeting the MDM2-p53 pathway in dedifferentiated liposarcoma.Frontiers in oncology · 2022Review
- p53 expression in repair/reactive renal tubular cells: A potential pitfall leading to a false-positive diagnosis of urine cytology.Cancer medicine · 2021Article
- Targeting Mouse Double Minute 2: Current Concepts in DNA Damage Repair and Therapeutic Approaches in Cancer.Frontiers in pharmacology · 2020Review
- Review
- p53 Is Active in Human Amniotic Fluid Stem Cells.Stem cells and development · 2018Article
- Novel isatin-derived molecules activate p53 via interference with Mdm2 to promote apoptosis.Cell cycle (Georgetown, Tex.) · 2018Article
- FKBP12 enhances sensitivity to chemotherapy-induced cancer cell apoptosis by inhibiting MDM2.Oncogene · 2017Article
- Ubiquitin-specific peptidase 48 regulates Mdm2 protein levels independent of its deubiquitinase activity.Scientific reports · 2017Article
- The IGF-1R/AKT pathway determines cell fate in response to p53.Translational cancer research · 2016Article
- Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis.Translational cancer research · 2016Article
- Li-Fraumeni Syndrome.Journal of pediatric genetics · 2016Review
- Regulation of MDM2 Stability After DNA Damage.Journal of cellular physiology · 2015Review
- The MDM2 RING domain and central acidic domain play distinct roles in MDM2 protein homodimerization and MDM2-MDMX protein heterodimerization.The Journal of biological chemistry · 2015Article
- p53 is active in murine stem cells and alters the transcriptome in a manner that is reminiscent of mutant p53.Cell death & disease · 2015Article
- MAGE-A Cancer/Testis Antigens Inhibit MDM2 Ubiquitylation Function and Promote Increased Levels of MDM4.PloS one · 2015Article
- Autoactivation of the MDM2 E3 ligase by intramolecular interaction.Molecular and cellular biology · 2014Article
- Scission of the p53-MDM2 Loop by Ribosomal Proteins.Genes & cancer · 2012Article
- The Roles of MDM2 and MDMX Phosphorylation in Stress Signaling to p53.Genes & cancer · 2012Article
4 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Mdm2 protein mediates ubiquitylation and degradation of p53 and is a key regulator of this tumor suppressor. More recently, it has been shown that Mdm2 is highly phosphorylated within its central acidic domain. In order to address the issue of how these modifications might regulate Mdm2 function, putative phosphorylation sites within this domain were substituted, individually or in pairs, with alanine residues. Mutants with serine-to-alanine substitutions between residues 244 and 260 abolished or at least reduced the capacity of Mdm2 to promote p53 degradation. In each case, loss of degradation function was independent of the ability to bind to p53 or p14ARF. Moreover, each of the Mdm2 mutants completely retained the capacity to act as a ubiquitin ligase in vivo. Thus, ubiquitylation and degradation can be uncoupled. Two-dimensional phosphopeptide mapping coupled with the use of phospho-specific antibodies revealed that Mdm2 is phosphorylated physiologically at several sites within this region, consistent with the idea that phosphorylation is important for Mdm2 activity. Strikingly, treatment of cells with ionizing radiation resulted in a significant decrease in the phosphorylation of residues that are important for p53 turnover. This hypophosphorylation preceded p53 accumulation. These findings indicate that Mdm2 contributes an additional function toward the degradation of p53 that is distinct from its ubiquitin ligase activity and is regulated by phosphorylation. Our model suggests that hypophosphorylation of Mdm2 in response to ionizing irradiation inactivates this novel function, thereby contributing to p53 stabilization.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.