No anti-apoptotic effects of single copies of mutant p53 genes in drug-treated tumor cells.
Some mutant forms of the p53 tumor suppressor have been documented to exert novel oncogenic functions including the increase of tumorigenicity, metastatic potential, genomic instability and therapy resistance of tumor cells. The latter has been suggested to be caused, primarily, by inhibition of apoptosis and, in part, through the activation of genes by mutant p53 whose products can counteract drug activities. Recently described in this context was the dUTPase, which may confer resistance to fluoropyrimidine drugs such as 5-fluorouracil (5-FU). We report here findings that call in question the existence of a direct anti-apoptotic effect of mutant p53. Wild-type p53-negative human fibroblasts, and Saos-2, H1299 and HCT116 tumor cells, treated with adriamycin, etoposide, cisplatin or 5-FU, failed to show apoptosis resistance when retrovirally bulk-infected to express the p53 mutants 175H or 273H at levels observed in naturally mutant p53-producing tumor cells. Furthermore, dUTPase gene expression was not stimulated by mutant p53, but instead by cellular events that involve DNA synthesis. We interpret the combined available data to suggest that much of the anti-apoptotic effect of mutant p53 is indirect and secondary to DNA-damaging and/or repair-interfering effects of these proteins.
Department of Virology, University of Saarland Medical School, Homburg/Saar, Germany.
Claudia
C
Fritzsche
Geraldine
G
Zeller
Karl X
KX
Knaup
Klaus
K
Roemer
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D005822:Genetic Vectors; D006801:Humans; D015151:Immunoblotting; D009154:Mutation; D011755:Pyrophosphatases / Q000235:genetics*; D012190:Retroviridae / Q000235:genetics; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase