Human and mouse Fas (APO-1/CD95) death receptor genes each contain a p53-responsive element that is activated by p53 mutants unable to induce apoptosis.
p53 is a tumor suppressor protein that induces apoptosis at least in part through its ability to act as a sequence-specific transactivator. This work reports that intron 1 of the mouse Fas death receptor gene contains a p53-responsive element (p53RE) that matches the p53 consensus sequence and that is located between nucleotides +1704 and +1723 from the transcription initiation site. This element is specifically bound by p53 and functions as a p53-dependent enhancer in mammalian or in yeast reporter gene assays. Contrary to bax, another known pro-apoptotic p53-target gene, both mouse and human FAS p53REs are still activated by the discriminatory p53 mutants Pro-175 and Ala-143, a class of mutants unable to induce apoptosis. We propose that p53-dependent up-regulation of Fas does not induce apoptosis per se but sensitizes the cell to other pro-apoptotic signal(s). The functional conservation of p53-dependent Fas up-regulation argues strongly in favor of its biological importance and suggests that murine models may be used to study further the in vivo role of Fas in the p53 response.
Munsch
D
D
Laboratoire de Cancérogenèse Moléculaire, UMR 217 du CNRS/Commissariat à l'Energie Atomique (CEA), Department de Radiobiologie et Radiopathologie, Direction des Sciences de la Vie, CEA, 92265 Fontenay-aux-Roses Cedex, France.
Watanabe-Fukunaga
R
R
Bourdon
J C
JC
Nagata
S
S
May
E
E
Yonish-Rouach
E
E
Reisdorf
P
P
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002460:Cell Line; D017930:Genes, Reporter; D006801:Humans; D051379:Mice; D009154:Mutation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D019014:fas Receptor / Q000235:genetics*
D016159:Tumor Suppressor Protein p53; D019014:fas Receptor