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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / genetics*
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Apoptosis Regulatory Proteins
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Calcium-Calmodulin-Dependent Protein Kinases / deficiency*
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Carrier Proteins*
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Cell Cycle Proteins*
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Cell Division / genetics
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Cell Line, Transformed / cytology
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Cell Line, Transformed / enzymology
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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DNA-Binding Proteins*
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Death-Associated Protein Kinases
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E2F Transcription Factors
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E2F1 Transcription Factor
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Fetus
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Fibroblasts / cytology
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Fibroblasts / enzymology
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Gene Expression Regulation, Neoplastic / physiology
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Genes, Tumor Suppressor / physiology*
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Genes, cdc / physiology*
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Genes, myc / physiology
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Mice
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Mice, Knockout
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Oncogenes / physiology
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Proteins / genetics
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Proteins / metabolism*
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Retinoblastoma-Binding Protein 1
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Signal Transduction / genetics
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Transcription Factor DP1
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Transcription Factors / genetics
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Tumor Suppressor Protein p14ARF
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Apoptosis Regulatory Proteins
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Arid4a protein, mouse
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Carrier Proteins
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Cell Cycle Proteins
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DNA-Binding Proteins
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E2F Transcription Factors
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E2F1 Transcription Factor
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E2f1 protein, mouse
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Proteins
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Retinoblastoma-Binding Protein 1
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Transcription Factor DP1
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Transcription Factors
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Tumor Suppressor Protein p14ARF
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Tumor Suppressor Protein p53
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Death-Associated Protein Kinases
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Calcium-Calmodulin-Dependent Protein Kinases