ArticleThe Journal of biological chemistry2013
Sequential inductions of the ZEB1 transcription factor caused by mutation of Rb and then Ras proteins are required for tumor initiation and progression.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 29 citations in OpenAlex.
- Bidirectional coupling among EMT, AXL-RB1 signaling and lineage switch drives resistance to osimertinib and worse clinical outcomes in NSCLC.bioRxiv : the preprint server for biology · 2026Article
- From Motor Proteins to Oncogenic Factors: The Evolving Role of Kinesin Superfamily Proteins in Breast Cancer Development.Molecular biotechnology · 2026Review
- RB1 loss induces quiescent state through downregulation of RAS signaling in mammary epithelial cells.Cancer science · 2024Article
- Intestinal Epithelial Cells Adapt to Chronic Inflammation through Partial Genetic Reprogramming.Cancers · 2023Article
- Maternal diabetes induces senescence and neural tube defects sensitive to the senomorphic rapamycin.Science advances · 2021Article
- Zeb1 promotes corneal neovascularization by regulation of vascular endothelial cell proliferation.Communications biology · 2020Article
- Suppression of KIF3A inhibits triple negative breast cancer growth and metastasis by repressing Rb-E2F signaling and epithelial-mesenchymal transition.Cancer science · 2020Article
- Convergence of therapy-induced senescence (TIS) and EMT in multistep carcinogenesis: current opinions and emerging perspectives.Cell death discovery · 2020Review
- Article
- The transcriptional factor ZEB1 represses Syndecan 1 expression in prostate cancer.Scientific reports · 2018Article
- Long noncoding RNA ZEB1-AS1 epigenetically regulates the expressions of ZEB1 and downstream molecules in prostate cancer.Molecular cancer · 2017Article
- Roles and epigenetic regulation of epithelial-mesenchymal transition and its transcription factors in cancer initiation and progression.Cellular and molecular life sciences : CMLS · 2016Review
- 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
- HBP1-mediated Regulation of p21 Protein through the Mdm2/p53 and TCF4/EZH2 Pathways and Its Impact on Cell Senescence and Tumorigenesis.The Journal of biological chemistry · 2016Article
- Myocyte enhancer factor 2C regulation of hepatocellular carcinoma via vascular endothelial growth factor and Wnt/β-catenin signaling.Oncogene · 2015Article
- An Rb1-dependent amplification loop between Ets1 and Zeb1 is evident in thymocyte differentiation and invasive lung adenocarcinoma.BMC molecular biology · 2015Article
- The ZEB1 transcription factor acts in a negative feedback loop with miR200 downstream of Ras and Rb1 to regulate Bmi1 expression.The Journal of biological chemistry · 2014Article
- EMT or EMT-Promoting Transcription Factors, Where to Focus the Light?Frontiers in oncology · 2014Review
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
Rb1 restricts cell cycle progression, and it imposes cell contact inhibition to suppress tumor outgrowth. It also triggers oncogene-induced senescence to block Ras mutation. Loss of the Rb1 pathway, which is a hallmark of cancer cells, then provides a permissive environment for Ras mutation, and Ras is sufficient for invasive tumor formation in Rb1 family mutant mouse embryo fibroblasts (MEFs). These results demonstrate that sequential mutation of the Rb1 and Ras pathways comprises a tumor initiation axis. Both Rb1 and Ras regulate expression of the transcription factor ZEB1, thereby linking tumor initiation to the subsequent invasion and metastasis, which is induced by ZEB1. ZEB1 acts in a negative feedback loop to block expression of miR-200, which is thought to facilitate tumor invasion and metastasis. However, ZEB1 also represses cyclin-dependent kinase (cdk) inhibitors to control the cell cycle; its mutation in MEFs leads to induction of these inhibitors and premature senescence. Here, we provide evidence for two sequential inductions of ZEB1 during Ras transformation of MEFs. Rb1 constitutively represses cdk inhibitors, and induction of ZEB1 when the Rb1 pathway is lost is required to maintain this repression, allowing for the classic immortalization and loss of cell contact inhibition seen when the Rb1 pathway is lost. In vivo, we show that this induction of ZEB1 is required for Ras-initiated tumor formation. ZEB1 is then further induced by Ras, beyond the level seen with Rb1 mutation, and this Ras superinduction is required to reach a threshold of ZEB1 sufficient for repression of miR-200 and tumor invasion.
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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.