ArticleThe EMBO journal2000
Smad2, Smad3 and Smad4 cooperate with Sp1 to induce p15(Ink4B) transcription in response to TGF-beta.
Article in The EMBO journal, 2000. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 141 papers.
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Who cites it
141 citing papers in PubMed, 394 citations in OpenAlex.
- Current Status of Intestinal Stem Cell Research: Mechanisms, Intestinal Diseases, and Organoid Development.Cells · 2026Review
- Promoter methylation correlates with reduced SMAD4 expression in patients with breast cancer.Discover oncology · 2025Article
- Cellular senescence mediates retinal ganglion cell survival regulation post-optic nerve crush injury.Cell proliferation · 2024Article
- Kinome-wide CRISPR-Cas9 screens revealedBiochemistry and biophysics reports · 2024Article
- Anticancer drugs: How to select small molecule combinations?Trends in pharmacological sciences · 2024Review
- TGF-β signaling in health, disease, and therapeutics.Signal transduction and targeted therapy · 2024Review
- Mast-cell expressed membrane protein-1 is expressed in classical monocytes and alveolar macrophages in idiopathic pulmonary fibrosis and regulates cell chemotaxis, adhesion, and migration in a TGFβ-dependent manner.American journal of physiology. Cell physiology · 2024Article
- Hepatitis B virus X protein and TGF-β: partners in the carcinogenic journey of hepatocellular carcinoma.Frontiers in oncology · 2024Review
- The Role of TGF-β/SMAD Signaling in Hepatocellular Carcinoma: from Mechanism to Therapy and Prognosis.International journal of biological sciences · 2024Review
- Kinome-wide CRISPR-Cas9 knockout screens revealed PLK1 as a therapeutic target for osteosarcoma.Cell death discovery · 2023Article
- TGF-β Signaling in Progression of Oral Cancer.International journal of molecular sciences · 2023Review
- SOX17 is a Critical Factor in Maintaining Endothelial Function in Pulmonary Hypertension by an Exosome-Mediated Autocrine Manner.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Boolean modeling of mechanosensitive epithelial to mesenchymal transition and its reversal.iScience · 2023Article
- Imatinib blocks tyrosine phosphorylation of Smad4 and restores TGF-β growth-suppressive signaling in BCR-ABL1-positive leukemia.Signal transduction and targeted therapy · 2023Article
- TGF-β2 Regulates Transcription of the KCells · 2022Article
- Exosomes rewire the cartilage microenvironment in osteoarthritis: from intercellular communication to therapeutic strategies.International journal of oral science · 2022Review
- Long noncoding RNA Smyca coactivates TGF-β/Smad and Myc pathways to drive tumor progression.Journal of hematology & oncology · 2022Article
- Realization of the T Lineage Program Involves GATA-3 Induction of Bcl11b and Repression of Cdkn2b Expression.Journal of immunology (Baltimore, Md. : 1950) · 2022Article
- Smad3 Phospho-Isoform Signaling in Nonalcoholic Steatohepatitis.International journal of molecular sciences · 2022Review
- Long noncoding RNA BCRP3 stimulates VPS34 and autophagy activities to promote protein homeostasis and cell survival.Journal of biomedical science · 2022Article
81 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Transforming growth factor-beta (TGF-beta) arrests growth of epithelial cells by inducing the transcription of p15(Ink4B), a cyclin-dependent kinase inhibitor. In this study, we demonstrate that p15(Ink4B) induction was mediated by a TGF-beta-induced complex of Smad2, Smad3, Smad4 and Sp1. Mutations in the Sp1- or Smad-binding sequences decreased or abolished the TGF-beta responsiveness of the p15(Ink4B) promoter. Interference with, or deficiency in, Smad2, Smad3 or Smad4 functions also reduced or abolished the TGF-beta-dependent p15(Ink4B) induction, whereas the absence of Sp1 reduced the basal and TGF-beta-induced p15(Ink4B) transcription. In the nucleoprotein complex, Smad2 interacted through its C-domain with Sp1 and enhanced the DNA binding and transcriptional activity of Sp1. Smad3 interacted indirectly with Sp1 through its association with Smad2 and/or Smad4, and bound directly to the p15(Ink4B) promoter. Finally, Smad4 interacted through its N-domain with Sp1. Our data demonstrate the physical interactions and functional cooperativity of Sp1 with a complex of Smad2, Smad3 and Smad4 in the induction of the p15(Ink4B) gene. These findings explain the tumor suppressor roles of Smad2 and Smad4 in growth arrest signaling by TGF-beta.
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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.