ArticleThe Journal of biological chemistry2014
The ZEB1 transcription factor acts in a negative feedback loop with miR200 downstream of Ras and Rb1 to regulate Bmi1 expression.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 44 citations in OpenAlex.
- A new digital droplet PCR method for looking at epigenetics in diffuse large B-cell lymphomas: The role of BMI1, EZH2, and USP22 genes.International journal of laboratory hematology · 2025Article
- Review
- RB1 loss induces quiescent state through downregulation of RAS signaling in mammary epithelial cells.Cancer science · 2024Article
- MiRNA-200b level in peripheral blood predicts renal interstitial injury in patients with diabetic nephropathy.Journal of medical biochemistry · 2023Article
- Spheroid-induced heterogeneity and plasticity of uveal melanoma cells.Cellular oncology (Dordrecht, Netherlands) · 2022Article
- Mitosis, a springboard for epithelial-mesenchymal transition?Cell cycle (Georgetown, Tex.) · 2021Article
- KSR1- and ERK-dependent translational regulation of the epithelial-to-mesenchymal transition.eLife · 2021Article
- Zeb1 induces immune checkpoints to form an immunosuppressive envelope around invading cancer cells.Science advances · 2021Article
- Zeb1 promotes corneal neovascularization by regulation of vascular endothelial cell proliferation.Communications biology · 2020Article
- RAS, Cellular Plasticity, and Tumor Budding in Colorectal Cancer.Frontiers in oncology · 2019Review
- Mechanistic regulation of epithelial-to-mesenchymal transition through RAS signaling pathway and therapeutic implications in human cancer.Journal of cell communication and signaling · 2018Review
- Mitotic polarization of transcription factors during asymmetric division establishes fate of forming cancer cells.Nature communications · 2018Article
- Functional Role of Non-Coding RNAs during Epithelial-To-Mesenchymal Transition.Non-coding RNA · 2018Review
- High expression of ZEB1 in endometriosis and its role in 17β-estradiol-induced epithelial-mesenchymal transition.International journal of clinical and experimental pathology · 2018Article
- Suppression of MicroRNA 200 Family Expression by Oncogenic KRAS Activation Promotes Cell Survival and Epithelial-Mesenchymal Transition in KRAS-Driven Cancer.Molecular and cellular biology · 2016Article
- Dephosphorylation of the Retinoblastoma protein (Rb) inhibits cancer cell EMT via Zeb.Cancer biology & therapy · 2016Article
- ZEB1 expression is increased in IDH1-mutant lower-grade gliomas.Journal of neuro-oncology · 2016Article
- Two-Step Reactivation of Dormant Cones in Retinitis Pigmentosa.Cell reports · 2016Article
- Connecting the dots: chromatin and alternative splicing in EMT.Biochemistry and cell biology = Biochimie et biologie cellulaire · 2016Review
- BMI1 induces an invasive signature in melanoma that promotes metastasis and chemoresistance.Genes & development · 2016Article
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
Ras mutations are frequent in cancer cells where they drive proliferation and resistance to apoptosis. However in primary cells, mutant Ras instead can cause oncogene-induced senescence, a tumor suppressor function linked to repression of the polycomb factor Bmi1, which normally regulates cell cycle inhibitory cyclin-dependent kinase inhibitors (cdki). It is unclear how Ras causes repression of Bmi1 in primary cells to suppress tumor formation while inducing the gene in cancer cells to drive tumor progression. Ras also induces the EMT transcription factor ZEB1 to trigger tumor invasion and metastasis. Beyond its well-documented role in EMT, ZEB1 is important for maintaining repression of cdki. Indeed, heterozygous mutation of ZEB1 is sufficient for elevated cdki expression, leading to premature senescence of primary cells. A similar phenotype is evident with Bmi1 mutation. We show that activation of Rb1 in response to mutant Ras causes dominant repression of ZEB1 in primary cells, but loss of the Rb1 pathway is a hallmark of cancer cells and in the absence of such Rb1 repression Ras induces ZEB1 in cancer cells. ZEB1 represses miR-200 in the context of a mutual repression loop. Because miR-200 represses Bmi1, induction of ZEB1 leads to induction of Bmi1. Rb1 pathway status then dictates the opposing effects of mutant Ras on the ZEB1-miR-200 loop in primary versus cancer cells. This loop not only triggers EMT, surprisingly we show it acts downstream of Ras to regulate Bmi1 expression and thus the critical decision between oncogene-induced senescence and tumor initiation.
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