DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation
Abstract
DAP kinase is a pro-apoptotic calcium-regulated serine/threonine kinase, whose expression is frequently lost in human tumours. Here we show that DAP kinase counteracts oncogene-induced transformation by activating a p19ARF/p53-dependent apoptotic checkpoint. Ectopic expression of DAP kinase suppressed oncogenic transformation of primary embryonic fibroblasts by activating p53 in a p19ARF-dependent manner. Consequently, the fibroblasts underwent apoptosis, characterized by caspase activation and DNA fragmentation. In response to c-Myc or E2F-1, the endogenous DAP kinase protein was upregulated. Furthermore, functional or genetic inactivation of the endogenous DAP kinase reduced the extent of induction of p19ARF/p53 and weakened the subsequent apoptotic responses to c-Myc or E2F-1. These results establish a role for DAP kinase in an early apoptotic checkpoint designed to eliminate pre-malignant cells during cancer development.
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In absence of ligands, UNC5B enables PP2A-mediated activating dephosphorylation of DAPK1, which promotes p53-dependent RCD.
“(3) UNC5B enables the protein phosphatase 2 (PP2A)-mediated activating dephosphorylation of death associated protein kinase 1 (DAPK1), which is known to promote p53-dependent RCD [355–357]”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [357]
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- Authors
- Raveh, T., Droguett, G., Horwitz, M. S., DePinho, R. A., & Kimchi, A.
- Affiliations
- Weizmann Institute of Science (IL)
- Albert Einstein College of Medicine (US)
- Harvard University (US)
- Corresponding author
- Kimchi, Adi
- Venue
- Nature Cell Biology
- Published
- 2000-11-22
- Volume
- 3
- Issue
- 1
- Pages
- 1-7
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W1493931678
- Cited by
- 361
- References
- 39
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 7 · 2023: 6 · 2022: 6 · 2021: 8 · 2020: 8 · 2019: 10 · 2018: 12 · 2017: 6 · 2016: 13 · 2015: 10 · 2014: 10 · 2013: 18 · 2012: 13
- FWCI
- 10.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Cancer Society
- Israel Academy of Sciences and Humanities
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- DAP kinase, p19ARF, p53, apoptosis, oncogenic transformation, c-Myc, E2F1, caspase activation, embryonic fibroblasts, premalignant cells, tumor suppression
- MeSH terms
- Animals, Carrier Proteins, Cell Division, Cell Line, Transformed, Cell Transformation, Neoplastic, DNA-Binding Proteins, Fetus, Fibroblasts, Oncogenes, Proteins, Transcription Factors, Signal Transduction, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Tumor Suppressor Protein p53, Genes, myc, Apoptosis, Calcium-Calmodulin-Dependent Protein Kinases, Mice, Knockout, Cell Cycle Proteins, Genes, cdc, Tumor Suppressor Protein p14ARF, Transcription Factor DP1, E2F Transcription Factors, E2F1 Transcription Factor, Apoptosis Regulatory Proteins, Mice, Retinoblastoma-Binding Protein 1, Death-Associated Protein Kinases
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