DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation.
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.
Raveh
T
T
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Droguett
G
G
Horwitz
M S
MS
DePinho
R A
RA
Kimchi
A
A
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000172:deficiency* / Q000235:genetics; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000235:genetics; D002461:Cell Line, Transformed / Q000166:cytology / Q000201:enzymology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D064550:Death-Associated Protein Kinases; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005333:Fetus; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D018816:Genes, cdc / Q000502:physiology*; D016259:Genes, myc / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009857:Oncogenes / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D056465:Retinoblastoma-Binding Protein 1; D015398:Signal Transduction / Q000235:genetics; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000235:genetics; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C533431:Arid4a protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D011506:Proteins; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases