ArticleThe Journal of biological chemistry2016
Human epidermal growth factor receptor 4 (Her4) Suppresses p53 Protein via Targeting the MDMX-MDM2 Protein Complex: IMPLICATION OF A NOVEL MDMX SER-314 PHOSPHOSITE.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 19 citations in OpenAlex.
- FLT4 activation promotes acute lymphoid leukemia survival through stabilization of MDM2/MDMX and inactivation of p53.Oncogenesis · 2025Article
- Structure and function of MDM2 and MDM4 in health and disease.The Biochemical journal · 2025Review
- HER4 Affects Sensitivity to Tamoxifen and Abemaciclib in Luminal Breast Cancer Cells and Restricts Tumor Growth in MCF-7-Based Humanized Tumor Mice.International journal of molecular sciences · 2024Article
- The Basally Expressed p53-Mediated Homeostatic Function.Frontiers in cell and developmental biology · 2021Review
- MDMX phosphorylation-dependent p53 downregulation contributes to an immunosuppressive tumor microenvironment.Journal of molecular cell biology · 2020Article
- The MDM2/MDMX/p53 axis in the adaptive stress response.Translational cancer research · 2020Review
- The long and the short of it: the MDM4 tail so far.Journal of molecular cell biology · 2019Review
- CDK4 inhibition diminishes p53 activation by MDM2 antagonists.Cell death & disease · 2018Article
- Article
- AXL receptor signalling suppresses p53 in melanoma through stabilization of the MDMX-MDM2 complex.Journal of molecular cell biology · 2017Article
- MDMX under stress: the MDMX-MDM2 complex as stress signals hub.Translational cancer research · 2016Article
- Her4 in gastric adenocarcinoma and its association with molecular prognostic markers Ki-67 proliferation index and p53 mutational status in Saudis: A study at a tertiary care hospital in Eastern Saudi Arabia.Journal of family & community medicineArticle
- Holistic Treatment Incorporating Moist Wound Healing for Postoperative Radiation-Induced Perineal Ulcer in Rectal Malignancy: A Case Report.Case reports in dermatologyArticle
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Deregulated receptor tyrosine kinase (RTK) signaling is frequently associated with tumorigenesis and therapy resistance, but its underlying mechanisms still need to be elucidated. In this study, we have shown that the RTK human epidermal growth factor receptor 4 (Her4, also known as Erbb4) can inhibit the tumor suppressor p53 by regulating MDMX-mouse double minute 2 homolog (MDM2) complex stability. Upon activation by either overexpression of a constitutively active vector or ligand binding (Neuregulin-1), Her4 was able to stabilize the MDMX-MDM2 complex, resulting in suppression of p53 transcriptional activity, as shown by p53-responsive element-driven luciferase assay and mRNA levels of p53 target genes. Using a phospho-proteomics approach, we functionally identified a novel Her4-induced posttranslational modification on MDMX at Ser-314, a putative phosphorylation site for the CDK4/6 kinase. Remarkably, inhibition of Ser-314 phosphorylation either with Ser-to-Ala substitution or with a specific inhibitor of CDK4/6 kinase blocked Her4-induced stabilization of MDMX-MDM2 and rescued p53 activity. Our study offers insights into the mechanisms of deregulated RTK-induced carcinogenesis and provides the basis for the use of inhibitors targeting RTK-mediated signals for p53 restoration.
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