Cited by 361Cancer-related Molecular PathwaysCell death mechanisms and regulationPI3K/AKT/mTOR signaling in cancer

DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation

Raveh, Tal, Droguett, Gustavo, Horwitz, Marshall S., DePinho, Ronald A., Kimchi, Adi·2001·Nature Cell Biology

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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Crossref · 10.1038/35050500

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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
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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