ArticleCell death & disease2013
AP4 directly downregulates p16 and p21 to suppress senescence and mediate transformation.
Article in Cell death & disease, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 39 citations in OpenAlex.
- A TFAP4-UBC9-SUMO1 axis orchestrates pathological mitochondrial hyperfission in diabetic complications.Acta diabetologica · 2026Article
- Myc and Skp2 overexpression promotes p27 ubiquitination and degradation in Ewing Sarcoma.PloS one · 2026Article
- Senescent endothelial cells: key commanders of the cellular communication network within atherosclerotic plaques.Frontiers in immunology · 2026Review
- Escape and evasion: when immunosurveillance of senescent cells goes wrong.Frontiers in genetics · 2026Review
- Systematic profiling reveals distinct senescence signatures and regulators across human brain cell types.Nature communications · 2025Article
- TFAP4 exacerbates pathological cardiac fibrosis by modulating mechanotransduction.Cell insight · 2025Article
- Regulatory Network Inference of Induced Senescent Midbrain Cell Types Reveals Cell Type-Specific Senescence-Associated Transcriptional Regulators.bioRxiv : the preprint server for biology · 2025Article
- The role and regulatory mechanism of lysosome associated protein transmembrane 4β in tumors.Frontiers in oncology · 2025Review
- Deletion of the transcriptional regulator TFAP4 accelerates c-MYC-driven lymphomagenesis.Cell death and differentiation · 2023Article
- Article
- AP4 suppresses DNA damage, chromosomal instability and senescence via inducing MDC1/Mediator of DNA damage Checkpoint 1 and repressing MIR22HG/miR-22-3p.Molecular cancer · 2022Article
- B7-H3 suppresses doxorubicin-induced senescence-like growth arrest in colorectal cancer through the AKT/TM4SF1/SIRT1 pathway.Cell death & disease · 2021Article
- Review
- Oridonin Dose-Dependently Modulates the Cell Senescence and Apoptosis of Gastric Cancer Cells.Evidence-based complementary and alternative medicine : eCAM · 2021Article
- The human amniotic fluid mesenchymal stem cells therapy on, SKOV3, ovarian cancer cell line.Molecular genetics & genomic medicine · 2019Article
- Intricate crosstalk between MYC and non-coding RNAs regulates hallmarks of cancer.Molecular oncology · 2019Review
- Transcription factor activating protein 4 is synthetically lethal and a master regulator of MYCN-amplified neuroblastoma.Oncogene · 2018Article
- Ap4 is rate limiting for intestinal tumor formation by controlling the homeostasis of intestinal stem cells.Nature communications · 2018Article
- Evaluating the prognostic value and functional roles of transcription factor AP4 in colorectal cancer.Oncology letters · 2018Article
- AP4 positively regulates LAPTM4B to promote hepatocellular carcinoma growth and metastasis, while reducing chemotherapy sensitivity.Molecular oncology · 2018Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Here we analyzed the function of the c-MYC-inducible basic helix-loop-helix leucine-zipper transcription factor AP4 in AP4-deficient mouse embryo fibroblasts (MEFs). Loss of AP4 resulted in premature senescence and resistance towards immortalization. Senescence was accompanied by induction of the cyclin-dependent kinase inhibitor-encoding genes p16, a known tumor suppressor, and p21, a previously described target for repression by AP4. Notably, AP4 directly repressed p16 expression via conserved E-box motifs in MEFs and human diploid fibroblasts. Senescence caused by AP4-deficiency was prevented by depletion of p16 and/or p21, demonstrating that these factors mediate senescence caused by AP4 loss. As senescence induced by the loss of AP4 was rescued by ectopic AP4, secondary lesions were not involved in causing premature senescence. Activation of c-MYC resulted in repression of p21 and p16 in AP4(+/+), but not in AP4(-/-) MEFs. Furthermore, after combined expression of c-MYC and mutant RAS in MEFs, AP4 was required for colony formation, anchorage-independent growth and tumor formation in mice. In addition, combined ectopic expression of AP4 and mutant RAS in MEFs resulted in colony formation. However, additional loss of the p53 tumor suppressor was necessary for anchorage-independent growth and tumor formation of MEFs by combined AP4 and mutant RAS expression. In conclusion, this study identified AP4 as an oncogenic antagonist of cellular senescence. AP4 achieves this effect by direct repression of p16 and p21, and may thereby critically contribute to c-MYC function and tumor progression.
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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.