Progression toward tumor cell phenotype is enhanced by overexpression of a mutant p53 tumor-suppressor gene isolated from nasopharyngeal carcinoma.
We recently reported the detection of a heterozygous G-->C point mutation at codon 280 of p53 in nasopharyngeal carcinoma, which causes an Arg-->Thr substitution. To test whether this mutant p53 has gained function as an oncogene, we overexpressed the mutant p53 in nontumorigenic cells of two model systems: (i) human Saos-2 cells lacking endogenous p53 and (ii) mouse JB6 variants that bear endogenous wild-type p53. Although they have no growth advantage over the neomycin controls in monolayer culture, human Saos-2 transfectants overexpressing mutant p53 do show enhanced progression to tumor cell phenotype, as assayed by anchorage-independent growth and in vivo tumorigenicity. The enhancement is seen only in transfectants expressing higher levels of p53 protein. In the mouse JB6 system, the mutant p53 functions dominantly in the presence of endogenous wild-type p53 to enhance progression of preneoplastic promotion-sensitive cells toward anchorage-independent phenotype. Mouse JB6 transfectants of mutant p53 are, however, not tumorigenic in nude mice. We conclude from these studies that the G-->C point mutation of p53 at codon 280 is a gain-of-function mutation that appears to operate dominantly and that the mutant p53-thr280 has only moderate oncogenic activity. This mutation may cooperate with other yet-to-be isolated genes in the genesis of nasopharyngeal carcinoma.
Sun
Y
Y
Biological Carcinogenesis and Development Program, Program Resources, Inc./DynCorp, Frederick, MD.
Nakamura
K
K
Wendel
E
E
Colburn
N
N
D000595:Amino Acid Sequence; D000704:Analysis of Variance; D000818:Animals; D001483:Base Sequence; D002455:Cell Division; D003062:Codon / Q000235:genetics; D015870:Gene Expression; D016158:Genes, p53; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000473:pathology; D009368:Neoplasm Transplantation; D010641:Phenotype; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D003062:Codon