Role of p53 in regulating constitutive and X-radiation-inducible CD95 expression and function in carcinoma cells.
The p53 tumor suppressor protein is known to regulate the expression of the CD95 (Fas/APO-1) death receptor in a small subset of normal cell types as well as in many cancer cell types. However, whether p53-dependent regulation of CD95 expression is consistently associated with increased susceptibility to CD95-mediated cell death is poorly understood. To address this issue, we examined constitutive and induced CD95 surface expression and function in wild-type p53-expressing carcinoma cells relative to their isogenic p53-inactivated counterparts. We compared HCT116 colorectal carcinoma cells with their p53 biallelic knock-outs and control-transfected MCF-7 breast carcinoma cells with MCF-7 cells expressing a miniprotein inhibitor of p53 (p53DD). In both cell lines, the constitutive expression of surface CD95 was significantly reduced in p53-inactivated cells, as was the apoptotic response to agonistic anti-CD95 antibody. In both cell lines, only cells with wild-type p53 activity exhibited up-regulation of surface CD95 after ionizing irradiation. Interestingly, induction of CD95 expression substantially enhanced the apoptotic response to CD95 ligation only in MCF-7 cells but not in HCT116 cells. These findings provide direct evidence for a major role for wild-type p53 activity in regulating constitutive expression and function of CD95 in carcinoma cells; however, they also demonstrate that the functional effect of DNA damage-induced up-regulation of CD95 may be cell type specific.
Sheard
Michael A
MA
Laboratory of Apoptosis Research, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic. msheard@chla.usc.edu
Uldrijan
Stjepan
S
Vojtesek
Borivoj
B
D017209:Apoptosis / Q000502:physiology / Q000528:radiation effects; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000502:physiology; D020868:Gene Silencing; D045325:HCT116 Cells; D006801:Humans; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology / Q000528:radiation effects; D014965:X-Rays; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D016159:Tumor Suppressor Protein p53; D019014:fas Receptor