Wild-type p53 can inhibit oncogene-mediated focus formation.
Mutant forms of the p53 cellular tumor antigen elicit neoplastic transformation in vitro. Recent evidence indicated that loss of normal p53 expression is a frequent event in certain types of tumors, raising the possibility that such loss provides transformed cells with a selective growth advantage. Thus, it was conceivable that the mutants might contribute to transformation by abrogating normal p53 function. We therefore studied the effect of plasmids encoding wild-type (wt) p53 on the ability of primary rat embryo fibroblasts to be transformed by a combination of mutant p53 and ras. It was found that wt p53 plasmids indeed caused a marked reduction in the number of transformed foci. Furthermore, wt p53 plasmids also suppressed the induction of transformed foci by combinations of bona fide oncogenes, such as myc plus ras or adenovirus E1A plus ras. On the other hand, plasmids carrying mutations in the p53 coding region totally failed to inhibit oncogene-mediated focus induction and often even slightly stimulated it. Hence, such mutations completely abolished the activity of wt p53 that is responsible for the "suppressor" effect. The latter fact is of special interest, since similar mutations in p53 are often observed in human and rodent tumors. The inhibitory effect of p53 was most pronounced when early-passage cells were used as targets, whereas established cell lines were less sensitive. These data support the notions that wt p53 expression may be restrictive to neoplastic progression and that p53 inactivation may play a crucial role in tumorigenesis.
Eliyahu
D
D
Department of Chemical Immunology, Weizmann Institute of Science, Rehovot, Israel.
Michalovitz
D
D
Eliyahu
S
S
Pinhasi-Kimhi
O
O
Oren
M
M
D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D011905:Genes, ras; D009154:Mutation; D009687:Nuclear Proteins / Q000502:physiology*; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D009857:Oncogenes; D010750:Phosphoproteins / Q000235:genetics / Q000502:physiology*; D010957:Plasmids; D051381:Rats; D011916:Rats, Inbred F344; D013489:Suppression, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53
D009687:Nuclear Proteins; D015513:Oncogene Proteins; D010750:Phosphoproteins; D016159:Tumor Suppressor Protein p53