ArticleProceedings of the National Academy of Sciences of the United States of America2006
Smad4 cooperates with lymphoid enhancer-binding factor 1/T cell-specific factor to increase c-myc expression in the absence of TGF-beta signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed.
- SKI is critical to counter TGF-β signaling to promote T cell function and autoimmunity.Science advances · 2026Article
- Nucleic Acid Therapeutics for "Undruggable" Cancer Targets: Mechanisms, Challenges, and Prospects.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- TGF-β signaling in health, disease, and therapeutics.Signal transduction and targeted therapy · 2024Review
- Sex-biased genome-editing effects of CRISPR-Cas9 across cancer cells dependent on p53 status.iScience · 2023Article
- Lateral confined growth of cells activates Lef1 dependent pathways to regulate cell-state transitions.Scientific reports · 2022Article
- Analysis of chromatin accessibility in p53 deficient spermatogonial stem cells for high frequency transformation into pluripotent state.Cell proliferation · 2022Article
- A SMAD4-modulated gene profile predicts disease-free survival in stage II and III colorectal cancer.Cancer reports (Hoboken, N.J.) · 2022Article
- Characterization and Validation of ceRNA-Mediated Pathway-Pathway Crosstalk Networks Across Eight Major Cardiovascular Diseases.Frontiers in cell and developmental biology · 2022Article
- Colorectal Cancer-Associated Smad4 R361 Hotspot Mutations Boost Wnt/β-Catenin Signaling through Enhanced Smad4-LEF1 Binding.Molecular cancer research : MCR · 2021Article
- Targeted sequencing of cancer-related genes in nasopharyngeal carcinoma identifies mutations in the TGF-β pathway.Cancer medicine · 2019Article
- A Reciprocal Role of the Smad4-Taz Axis in Osteogenesis and Adipogenesis of Mesenchymal Stem Cells.Stem cells (Dayton, Ohio) · 2019Article
- SMAD4 promotes TGF-β-independent NK cell homeostasis and maturation and antitumor immunity.The Journal of clinical investigation · 2018Article
- Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase.Scientific reports · 2016Article
- The transcription factor lymphoid enhancer factor 1 controls invariant natural killer T cell expansion and Th2-type effector differentiation.The Journal of experimental medicine · 2015Article
- Article
- Aptamers and their potential to selectively target aspects of EGF, Wnt/β-catenin and TGFβ-smad family signaling.International journal of molecular sciences · 2013Review
- Transforming growth factor-β activates c-Myc to promote palatal growth.Journal of cellular biochemistry · 2012Article
- Induction of a mesenchymal expression program in lung epithelial cells by wingless protein (Wnt)/β-catenin requires the presence of c-Jun N-terminal kinase-1 (JNK1).American journal of respiratory cell and molecular biology · 2012Article
- Smad4-mediated signaling inhibits intestinal neoplasia by inhibiting expression of β-catenin.Gastroenterology · 2012Article
- ChIP-seq defined genome-wide map of TGFβ/SMAD4 targets: implications with clinical outcome of ovarian cancer.PloS one · 2011Article
Corrections and comments
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Authors and funding
2 authors.
Funding
Abstract
The c-myc protooncogene is a key regulator of cell proliferation whose expression is reduced in normal epithelial cells in response to the growth inhibitory cytokine TGF-beta. Smad4 mediates this inhibitory effect of TGF-beta by forming a complex with Smad3, E2F4/5, and p107 at the TGF-beta inhibitory element (TIE) element on the c-myc promoter. In contrast, cell proliferation and c-myc expression are increased in response to Wnt ligands; this effect is mediated through the lymphoid enhancer-binding factor 1/T cell-specific factor (LEF/TCF) family of transcription factors on the c-myc promoter LEF/TCF-binding elements (TBE1 and TBE2). We report that a peptide aptamer designed to inhibit the binding between Smad4 and LEF/TCF reduced c-myc expression and the growth rate of HepG2 cells. Further analysis demonstrated that, in the absence of TGF-beta, Smad4 was bound to the positive regulatory element TBE1 from the c-myc promoter and activated c-myc promoter activity. Smad4 binding to the positive TBE1 c-myc element was reduced by TGF-beta, consistent with Smad4's inhibitory role on c-myc expression in response to TGF-beta. Reduction of Smad4 levels by RNAi knockdown also reduced c-myc expression levels and sensitized hepatocytes to cell death by serum deprivation. Two tumor-derived mutant Smad4 proteins that fail to mediate TGF-beta responses were still competent to cooperate with LEF1 to activate the c-myc promoter. These results support a previously unreported TGF-beta-independent function for Smad4 in cooperating with LEF/TCF to activate c-myc expression.
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