ArticleThe Journal of biological chemistry2011
c-Abl phosphorylation of Mdm2 facilitates Mdm2-Mdmx complex formation.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 30 citations in OpenAlex.
- p53 promotes its own polyubiquitination by enhancing the HDM2 and HDMX interaction.Protein science : a publication of the Protein Society · 2018Article
- The fate of murine double minute X (MdmX) is dictated by distinct signaling pathways through murine double minute 2 (Mdm2).Oncotarget · 2017Article
- Early-Stage Metastasis Requires Mdm2 and Not p53 Gain of Function.Molecular cancer research : MCR · 2017Article
- The Role of MDM2 in Promoting Genome Stability versus Instability.International journal of molecular sciences · 2017Review
- Combination therapy in a xenograft model of glioblastoma: enhancement of the antitumor activity of temozolomide by an MDM2 antagonist.Journal of neurosurgery · 2017Article
- Phosphorylation of the Mdm2 oncoprotein by the c-Abl tyrosine kinase regulates p53 tumor suppression and the radiosensitivity of mice.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis.Translational cancer research · 2016Article
- Intra molecular interactions in the regulation of p53 pathway.Translational cancer research · 2016Article
- c-Abl inhibits breast cancer tumorigenesis through reactivation of p53-mediated p21 expression.Oncotarget · 2016Article
- Allosteric Interactions by p53 mRNA Govern HDM2 E3 Ubiquitin Ligase Specificity under Different Conditions.Molecular and cellular biology · 2016Article
- Article
- Regulation of MDM2 Stability After DNA Damage.Journal of cellular physiology · 2015Review
- Src phosphorylation converts Mdm2 from a ubiquitinating to a neddylating E3 ligase.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Interplay between Mdm2 and HIPK2 in the DNA damage response.Journal of the Royal Society, Interface · 2014Article
- Inhibition of MDM2 by nilotinib contributes to cytotoxicity in both Philadelphia-positive and negative acute lymphoblastic leukemia.PloS one · 2014Article
- MDM2 and MDMX: Alone and together in regulation of p53.Translational cancer research · 2012Article
- The Roles of MDM2 and MDMX Phosphorylation in Stress Signaling to p53.Genes & cancer · 2012Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Mdm2 and Mdmx are oncoproteins that have essential yet nonredundant roles in development and function as part of a multicomponent ubiquitinating complex that targets p53 for proteasomal degradation. However, in response to DNA damage, Mdm2 and Mdmx are phosphorylated and protect p53 through various mechanisms. It has been predicted that Mdm2-Mdmx complex formation modulates Mdm2 ligase activity, yet the mechanism that promotes formation of Mdm2-Mdmx complexes is unknown. Here, we show that optimal Mdm2-Mdmx complex formation requires c-Abl phosphorylation of Mdm2 both in vitro and in vivo. In addition, Abl phosphorylation of Mdm2 is required for efficient ubiquitination of Mdmx in vitro, and eliminating c-Abl signaling, using c-Abl(-/-) knock-out murine embryonic fibroblasts, led to a decrease in Mdmx ubiquitination. Further, p53 levels are not induced as efficiently in c-Abl(-/-) murine embryonic fibroblasts following DNA damage. Overall, these results define a direct link between genotoxic stress-activated c-Abl kinase signaling and Mdm2-Mdmx complex formation. Our results add an important regulatory mechanism for the activation of p53 in response to DNA damage.
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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.