Hypoxia induces p53-dependent transactivation and Fas/CD95-dependent apoptosis.
p53 triggers apoptosis in response to cellular stress. We analyzed p53-dependent gene and protein expression in response to hypoxia using wild-type p53-carrying or p53 null HCT116 colon carcinoma cells. Hypoxia induced p53 protein levels and p53-dependent apoptosis in these cells. cDNA microarray analysis revealed that only a limited number of genes were regulated by p53 upon hypoxia. Most classical p53 target genes were not upregulated. However, we found that Fas/CD95 was significantly induced in response to hypoxia in a p53-dependent manner, along with several novel p53 target genes including ANXA1, DDIT3/GADD153 (CHOP), SEL1L and SMURF1. Disruption of Fas/CD95 signalling using anti-Fas-blocking antibody or a caspase 8 inhibitor abrogated p53-induced apoptosis in response to hypoxia. We conclude that hypoxia triggers a p53-dependent gene expression pattern distinct from that induced by other stress agents and that Fas/CD95 is a critical regulator of p53-dependent apoptosis upon hypoxia.
Liu
T
T
Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institute, Stockholm, Sweden.
Laurell
C
C
Selivanova
G
G
Lundeberg
J
J
Nilsson
P
P
Wiman
K G
KG
D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D015152:Blotting, Northern; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D006801:Humans; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000502:physiology; D019014:fas Receptor / Q000378:metabolism* / Q000502:physiology
D016159:Tumor Suppressor Protein p53; D019014:fas Receptor