Document Detail


DAP kinase activates a p19ARF/p53-mediated apoptotic checkpoint to suppress oncogenic transformation.
MedLine Citation:
PMID:  11146619     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
T Raveh; G Droguett; M S Horwitz; R A DePinho; A Kimchi
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Nature cell biology     Volume:  3     ISSN:  1465-7392     ISO Abbreviation:  Nat. Cell Biol.     Publication Date:  2001 Jan 
Date Detail:
Created Date:  2001-01-26     Completed Date:  2001-03-08     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  100890575     Medline TA:  Nat Cell Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1-7     Citation Subset:  IM    
Affiliation:
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / genetics*
Apoptosis Regulatory Proteins
Calcium-Calmodulin-Dependent Protein Kinases / deficiency*,  genetics
Carrier Proteins*
Cell Cycle Proteins*
Cell Division / genetics
Cell Line, Transformed / cytology,  enzymology
Cell Transformation, Neoplastic / genetics,  metabolism*
DNA-Binding Proteins*
E2F Transcription Factors
E2F1 Transcription Factor
Fetus
Fibroblasts / cytology,  enzymology
Gene Expression Regulation, Neoplastic / physiology
Genes, Tumor Suppressor / physiology*
Genes, cdc / physiology*
Genes, myc / physiology
Mice
Mice, Knockout
Oncogenes / physiology
Proteins / genetics,  metabolism*
Retinoblastoma-Binding Protein 1
Signal Transduction / genetics
Transcription Factor DP1
Transcription Factors / genetics
Tumor Suppressor Protein p14ARF
Tumor Suppressor Protein p53 / genetics,  metabolism*
Chemical
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/Arid4a protein, mouse; 0/Carrier Proteins; 0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/E2F Transcription Factors; 0/E2F1 Transcription Factor; 0/E2f1 protein, mouse; 0/Proteins; 0/Retinoblastoma-Binding Protein 1; 0/Transcription Factor DP1; 0/Transcription Factors; 0/Tumor Suppressor Protein p14ARF; 0/Tumor Suppressor Protein p53; EC 2.7.11.1/death-associated protein kinase; EC 2.7.11.17/Calcium-Calmodulin-Dependent Protein Kinases

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