ROLE OF P53 MUTATION IN POLYOMAVIRUS-INDUCED TUMORIGENESIS

Small DNA tumour viruses, such as simian virus 40 (SV40), papilloma vi ruses and adenoviruses, encode proteins that form complexes with and i nactivate the p53 and retinoblastoma (RB) proteins, This convergent ev olution reflects the common need of these viruses to inactivate these two important regulators of cell cycle progression and cell survival, Polyomavirus, a close relative of SV40, is different. Its large T prot ein complexes only with RB, not with p53, We have examined whether thi s is compensated by the frequent appearance of p53 mutations in polyom avirus-induced tumours, We tested the p53 status of 15 polyomavirus-in duced sarcomas, Two sarcomas were p53-negative while six carried mutan t p53, Another six sarcomas expressed low levels of wild-type p53, One tumour expressed high levels of wild-type p53 protein as shown by DNA sequencing and immunofluorescence staining, MDM2 amplification was no t detected in any of the tumours, but Northern blotting showed that MD M2 was overexpressed in at least two tumours that expressed wild-type p53 and in one tumour that expressed both wild-type and mutant p53, Tr eatment with the DNA-damaging agent mitomycin C caused p53 protein acc umulation followed by induction of MDM2 and WAF1/p21 mRNA in four of t he tumours expressing wild-type p53, indicating that p53-mediated tran scriptional activation was unaltered in these tumours, However, p53-me diated transactivation of WAF1/p21 was impaired in the wild-type p53-e xpressing tumours that expressed elevated levels of MDM2, These result s demonstrate that p53 mutation and inactivation are frequently but no t invariably involved in polyomavirus-induced tumorigenesis.