Switching mechanisms of cell death in mdm2- and mdm4-null mice by deletion of p53 downstream targets.
The p53 tumor suppressor ensures maintenance of genome integrity by initiating either apoptosis or cell cycle arrest in response to DNA damage. Deletion of either mdm2 or mdm4 genes, which encode p53 inhibitors, results in embryonic lethality. The lethal phenotypes are rescued in the absence of p53, which indicates that increased activity of p53 is the cause of lethality in the mdm2- and mdm4-null embryos. Here we show that mdm2-null embryos die because of apoptosis initiated at 3.5 days postcoitum (dpc). Partial rescue of mdm2-null embryos by deletion of bax allows survival to 6.5 dpc and alters the mechanism of death from apoptosis to cell cycle arrest, indicating that bax is a critical component of the p53 pathway in early embryogenesis. The death of mdm4-null embryos is due to p53-initiated cell cycle arrest at 7.5 dpc. Deletion of p21(p21(waf1/cip1)), a p53 downstream target partially responsible for cell cycle arrest, does not rescue this phenotype; however, deletion of p21 alters the mechanism of cell death from lack of proliferation to apoptosis. Thus, in both examples, deletion of a p53 downstream target gene allows p53 to redirect its efforts, highlighting a high degree of plasticity in p53 function.
Chavez-Reyes
Arturo
A
Department of Molecular Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Parant
John M
JM
Amelse
Lisa L
LL
de Oca Luna
Roberto Montes
RM
Korsmeyer
Stanley J
SJ
Lozano
Guillermina
G
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D003433:Crosses, Genetic; D004622:Embryo, Mammalian; D005260:Female; D017353:Gene Deletion; D016158:Genes, p53 / Q000502:physiology*; D008297:Male; D051379:Mice; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; C461497:Mdm4 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases