ArticleThe Journal of biological chemistry2015
The MDM2 RING domain and central acidic domain play distinct roles in MDM2 protein homodimerization and MDM2-MDMX protein heterodimerization.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed.
- MDM4 at the Crossroads: Beyond p53 and MDM2.Cancers · 2026Review
- Structure and function of MDM2 and MDM4 in health and disease.The Biochemical journal · 2025Review
- Upregulation of YPEL3 expression and induction of human breast cancer cell death by microRNAs.Toxicological research · 2024Article
- Ribosomal Protein S4 X-Linked as a Novel Modulator of MDM2 Stability by Suppressing MDM2 Auto-Ubiquitination and SCF Complex-Mediated Ubiquitination.Biomolecules · 2024Article
- MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future.Pharmacological reviews · 2024Review
- Role and therapeutic potential of E3s in the tumor microenvironment of hepatocellular carcinoma.Frontiers in immunology · 2024Review
- E3 ubiquitin ligases: key regulators of osteogenesis and potential therapeutic targets for bone disorders.Frontiers in cell and developmental biology · 2024Review
- MDMX in Cancer: A Partner of p53 and a p53-Independent Effector.Biologics : targets & therapy · 2024Review
- Advancements in MDM2 inhibition: Clinical and pre-clinical investigations of combination therapeutic regimens.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2023Review
- Zooming into the structure-function of RING finger proteins for anti-cancer therapeutic applications.American journal of cancer research · 2023Review
- Therapeutic Strategies to Activate p53.Pharmaceuticals (Basel, Switzerland) · 2022Review
- It's Getting Complicated-A Fresh Look at p53-MDM2-ARF Triangle in Tumorigenesis and Cancer Therapy.Frontiers in cell and developmental biology · 2022Review
- The roles of E3 ligases in Hepatocellular carcinoma.American journal of cancer research · 2022Review
- The roles and regulation of MDM2 and MDMX: it is not just about p53.Genes & development · 2021Review
- MDMX Recruits UbcH5c to Facilitate MDM2 E3 Ligase Activity and Subsequent p53 DegradationCancer research · 2021Article
- Functional roles of E3 ubiquitin ligases in gastric cancer.Oncology letters · 2020Review
- Mdm2: Open questions.Cancer science · 2020Review
- Entire ABL1 Gene Deletion Without BCR/ABL1 Rearrangement in a Female Patient with B-Cell Precursor Acute Lymphoblastic Leukemia.OncoTargets and therapy · 2020Article
- Targeting MDMX for Cancer Therapy: Rationale, Strategies, and Challenges.Frontiers in oncology · 2020Review
- Zinc-finger protein p52-ZER6 accelerates colorectal cancer cell proliferation and tumour progression through promoting p53 ubiquitination.EBioMedicine · 2019Article
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3 authors.
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Abstract
The oncoprotein murine double minute 2 (MDM2) is an E3 ligase that plays a prominent role in p53 suppression by promoting its polyubiquitination and proteasomal degradation. In its active form, MDM2 forms homodimers as well as heterodimers with the homologous protein murine double minute 4 (MDMX), both of which are thought to occur through their respective C-terminal RING (really interesting new gene) domains. In this study, using multiple MDM2 mutants, we show evidence suggesting that MDM2 homo- and heterodimerization occur through distinct mechanisms because MDM2 RING domain mutations that inhibit MDM2 interaction with MDMX do not affect MDM2 interaction with WT MDM2. Intriguingly, deletion of a portion of the MDM2 central acidic domain selectively inhibits interaction with MDM2 while leaving intact the ability of MDM2 to interact with MDMX and to ubiquitinate p53. Further analysis of an MDM2 C-terminal deletion mutant reveals that the C-terminal residues of MDM2 are required for both MDM2 and MDMX interaction. Collectively, our results suggest a model in which MDM2-MDMX heterodimerization requires the extreme C terminus and proper RING domain structure of MDM2, whereas MDM2 homodimerization requires the extreme C terminus and the central acidic domain of MDM2, suggesting that MDM2 homo- and heterodimers utilize distinct MDM2 domains. Our study is the first to report mutations capable of separating MDM2 homo- and heterodimerization.
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