dapk1, encoding an activator of a p19ARF-p53-mediated apoptotic checkpoint, is a transcription target of p53.
The p53 tumour suppressor functions as a transcriptional activator, and several p53-inducible genes that play a critical proapoptotic role have been described. Moreover, p53 regulates the expression of various proteins participating in autoregulatory feedback loops, including proteins that negatively control p53 stability (Mdm2 and Pirh2) or modulate stress-induced phosphorylation of p53 on Ser-46 (p53DINP1 or Wip1), a key event for p53-induced apoptosis. Here, we describe a new systematic analysis of p53 targets using oligonucleotide chips, and report the identification of dapk1 as a novel p53 target. We demonstrate that dapk1 mRNA levels increase in a p53-dependent manner in various cellular settings. Both human and mouse dapk1 genomic loci contain DNA sequences that bind p53 in vitro and in vivo. Since dapk1 encodes a serine/threonine kinase previously shown to suppress oncogene-induced transformation by activating a p19ARF/p53-dependent apoptotic checkpoint, our results suggest that Dapk1 participates in a new positive feedback loop controlling p53 activation and apoptosis.
Martoriati
Alain
A
Laboratory for Molecular Cancer Biology, Flanders Interuniversity Institute for Biotechnology (VIB), Technologiepark, 927, Ghent B-9052, Belgium.
Doumont
Gilles
G
Alcalay
Myriam
M
Bellefroid
Eric
E
Pelicci
Pier Giuseppe
PG
Marine
Jean-Christophe
JC
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019941:Cyclin-Dependent Kinase Inhibitor p16; D064550:Death-Associated Protein Kinases; D004622:Embryo, Mammalian / Q000737:chemistry / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007438:Introns / Q000235:genetics; D051379:Mice; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D014158:Transcription, Genetic; D025803:Tumor Suppressor Protein p14ARF / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases
D051017:Apoptosis Regulatory Proteins; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C461497:Mdm4 protein, mouse; C489428:Myc protein, mouse; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; C579096:DAPK1 protein, human; C579106:Dapk1 protein, mouse; D064550:Death-Associated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases