ArticleProceedings of the National Academy of Sciences of the United States of America2015
Src phosphorylation converts Mdm2 from a ubiquitinating to a neddylating E3 ligase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 34 citations in OpenAlex.
- Opportunities in cancer gene therapy: inhibiting MDM2 and restoring p14ARF as a means to activate p53.Molecular and cellular biochemistry · 2026Review
- Von Hippel-Lindau/Hypoxia Inducible Factor Axis in Glioblastoma.International journal of molecular sciences · 2025Review
- Induction of the Mdm2 gene and protein by kinase signaling pathways is repressed by the pVHL tumor suppressor.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Beyond genetics: driving cancer with the tumour microenvironment behind the wheel.Nature reviews. Cancer · 2024Review
- Effects of neddylation on viral infection: an overview.Archives of virology · 2023Review
- Discovery of neddylation E2s inhibitors with therapeutic activity.Oncogenesis · 2023Review
- MDM2 inhibition is synthetic lethal with PTEN loss in colorectal cancer cells via the p53-dependent mechanism.International journal of biological sciences · 2023Article
- The Four Homeostasis Knights: In Balance upon Post-Translational Modifications.International journal of molecular sciences · 2022Review
- SUMOylation and NEDDylation in Primary and Metastatic Cancers to Bone.Frontiers in cell and developmental biology · 2022Review
- Review
- The roles and regulation of MDM2 and MDMX: it is not just about p53.Genes & development · 2021Review
- Regulation of p53 by E3s.Cancers · 2021Review
- Molecular Mechanisms of Senescence and Implications for the Treatment of Myeloid Malignancies.Cancers · 2021Review
- Article
- Phosphorylation Modifications Regulating Cardiac Protein Quality Control Mechanisms.Frontiers in physiology · 2020Review
- Neddylation: A Versatile Pathway Takes on Chronic Liver Diseases.Frontiers in medicine · 2020Review
- P53, GHRH, inflammation and cancer.EBioMedicine · 2018Review
- Mutant and wild-type p53 form complexes with p73 upon phosphorylation by the kinase JNK.Science signaling · 2018Article
- Protein neddylation and its alterations in human cancers for targeted therapy.Cellular signalling · 2018Review
- SRC IncreasesMolecular and cellular biology · 2018Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Murine double minute-2 protein (Mdm2) is a multifaceted phosphorylated protein that plays a role in regulating numerous proteins including the tumor suppressor protein p53. Mdm2 binds to and is involved in conjugating either ubiquitin or Nedd8 (Neural precursor cell expressed, developmentally down-regulated 8) to p53. Although regulation of the E3 ubiquitin activity of Mdm2 has been investigated, regulation of the neddylating activity of Mdm2 remains to be defined. Here we show that activated c-Src kinase phosphorylates Y281 and Y302 of Mdm2, resulting in an increase in Mdm2 stability and its association with Ubc12, the E2 enzyme of the neddylating complex. Mdm2-dependent Nedd8 conjugation of p53 results in transcriptionally inactive p53, a process that is reversed with a small molecule inhibitor to either Src or Ubc12. Thus, our studies reveal how Mdm2 may neutralize and elevate p53 in actively proliferating cells and also provides a rationale for using therapies that target the Nedd8 pathway in wild-type p53 tumors.
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Registered trials
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.