ArticleOncogene2016
Scaffold protein FHL2 facilitates MDM2-mediated degradation of IER3 to regulate proliferation of cervical cancer cells.
Article in Oncogene, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26 citing papers in PubMed, 36 citations in OpenAlex.
- FHL2 production enabled new insight into its flexibility and unexpected binding stoichiometry with β-catenin.Journal of structural biology: X · 2026Article
- Integrated multi-omics analysis reveals the molecular landscape and therapeutic strategies in Chinese cervical cancer patients.PLoS biology · 2026Article
- FHL2 enhances ITGB1-mediated ECM remodeling and cellular stiffness to promote radioresistance in non-small cell lung cancer.Cell death discovery · 2025Article
- Single-Cell Dissection of the Serrated Pathway: Cellular Heterogeneity and Genetic Causality in Colorectal Cancer.International journal of molecular sciences · 2025Article
- Knockdown of IER3 Promotes Osteogenic Differentiation of Human Mesenchymal Stem Cells.Biomedicines · 2025Article
- The roles of FHL2 as a mechanotransducer for cellular functions in the mechanical environment.Frontiers in cell and developmental biology · 2024Review
- The roles of FHL2 in cancer.Clinical and experimental medicine · 2023Review
- Comprehensive pan-cancer analysis identifies FHL2 associated with poor prognosis in lung adenocarcinoma.Translational cancer research · 2023Article
- HBXIP knockdown inhibits FHL2 to promote cycle arrest and suppress cervical cancer cell proliferation, invasion and migration.Oncology letters · 2023Article
- Induced Coma, Death, and Organ Transplantation: A Physiologic, Genetic, and Theological Perspective.International journal of molecular sciences · 2023Review
- Review
- TAB182 aggravates progression of esophageal squamous cell carcinoma by enhancing β-catenin nuclear translocation through FHL2 dependent manner.Cell death & disease · 2022Article
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- Targeting FHL2-E-cadherin axis by miR-340-5p attenuates colon cancer cell migration and invasion.Oncology letters · 2021Article
- TRAIL promotes hepatocellular carcinoma apoptosis and inhibits proliferation and migration via interacting with IER3.Cancer cell international · 2021Article
- An alternative miRISC targets a cancer-associated coding sequence mutation in FOXL2.The EMBO journal · 2020Article
- Identification and validation of a six-gene signature associated with glycolysis to predict the prognosis of patients with cervical cancer.BMC cancer · 2020Article
- FOXL2 directs DNA double-strand break repair pathways by differentially interacting with Ku.Nature communications · 2020Article
- Deletion of the FHL2 gene attenuates intima-media thickening in a partially ligated carotid artery ligated mouse model.Journal of cellular and molecular medicine · 2020Article
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Authors and funding
8 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The expression of immediate early response 3 (IER3), a protein with a short half-life, is rapidly induced by various cellular stimuli. We recently reported that IER3 induces the apoptosis of cervical cancer cells and that its expression is downregulated in patients with cervical cancer. However, the molecular mechanism involved in the rapid degradation of IER3 remains unknown. Here, we demonstrate that MDM2 is an E3 ligase that interacts with IER3 and promotes its ubiquitination, followed by proteasomal degradation. Polyubiquitination of the conserved lysine 60 of IER3 is essential for its degradation. In addition, four and a half LIM domains protein 2 (FHL2) binds to both IER3 and MDM2, allowing for efficient MDM2-mediated IER3 degradation by facilitating an association between MDM2 and IER3. Moreover, IER3 induces cell cycle arrest in cervical cancer cells and its activity is further enhanced in cells in which FHL2 or MDM2 was silenced, thereby preventing IER3 degradation. The E6 and E7 oncoproteins of human papilloma virus 18 regulated IER3 expression. FHL2 expression was significantly higher in the squamous epithelium of cervical carcinoma tissues than in non-cancerous cervical tissues, whereas cervical carcinoma expression of IER3 was downregulated in this region. Thus, we determined the molecular mechanism responsible for IER3 degradation, involving a ternary complex of IER3, MDM2 and FHL2, which may contribute to cervical tumor growth. Furthermore, we demonstrated that FHL2 serves as a scaffold for E3 ligase and its substrate during the ubiquitination reaction, a function that has not been previously reported for this protein.
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