Tissue and cell-specific expression of the p53-target genes: bax, fas, mdm2 and waf1/p21, before and following ionising irradiation in mice.
The mechanisms by which the p53 tumour suppressor protein would, in vivo, co-ordinate the adaptive response to genotoxic stress is poorly understood. p53 has been shown to transactivate several genes that could be involved in two main cellular responses, growth arrest and apoptosis. To get further insight into the tissue-specific regulation of p53 transcriptional activity, we performed an extensive study looking at the expression of four well characterized p53-responsive genes, before and after gamma-irradiation in p53 wild-type (p53+/+) and p53-deficient (p53-/-) mice. The waf1, bax, fas and mdm2 genes were chosen for their different potential roles in the cellular response to stress. Our data demonstrate the strict p53-dependence of mRNA up-regulation for bax, fas and mdm2 in irradiated tissues and confirm such findings for waf1. They further highlight complex levels of regulatory mechanisms that could lead, in vivo, to selective transcriptional activation of genes by p53. In addition, our results provide arguments for the involvement of p53 in the basal mRNA expression of the four genes in some organs. Finally, in situ expression of Bax and p21Waf-1 protein suggests, at least in lymphoid organs, a direct correlation between selective p53-target gene expression and a particular response of a cell to ionising radiation.
Bouvard
V
V
Laboratoire de Cancérogenèse Moléculaire, UMR 217 CEA-CNRS, DRR, DSV, Centre d'Etude Nucleaire, Fontenay aux Roses, France.
Zaitchouk
T
T
Vacher
M
M
Duthu
A
A
Canivet
M
M
Choisy-Rossi
C
C
Nieruchalski
M
M
May
E
E
D000818:Animals; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics* / Q000528:radiation effects; D005720:Gamma Rays; D007150:Immunohistochemistry; D008221:Lymphoid Tissue / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins; D009928:Organ Specificity / Q000235:genetics / Q000528:radiation effects; D018384:Oxidative Stress / Q000528:radiation effects; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000528:radiation effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics* / Q000528:radiation effects; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000096:biosynthesis / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology*; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000235:genetics* / Q000528:radiation effects
C494827:Bax protein, mouse; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2