Role of p53 mutation in polyomavirus-induced tumorigenesis.
Small DNA tumour viruses, such as simian virus 40 (SV40), papilloma viruses and adenoviruses, encode proteins that form complexes with and inactivate the p53 and retinoblastoma (RB) proteins. This convergent evolution 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 protein complexes only with RB, not with p53. We have examined whether this is compensated by the frequent appearance of p53 mutations in polyomavirus-induced tumours. We tested the p53 status of 15 polyomavirus-induced sarcomas. Two sarcomas were p53-negative while six carried mutant 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 not detected in any of the tumours, but Northern blotting showed that MDM2 was overexpressed in at least two tumours that expressed wild-type p53 and in one tumour that expressed both wild-type and mutant p53. Treatment with the DNA-damaging agent mitomycin C caused p53 protein accumulation followed by induction of MDM2 and WAF1/p21 mRNA in four of the tumours expressing wild-type p53, indicating that p53-mediated transcriptional activation was unaltered in these tumours. However, p53-mediated transactivation of WAF1/p21 was impaired in the wild-type p53-expressing tumours that expressed elevated levels of MDM2. These results demonstrate that p53 mutation and inactivation are frequently but not invariably involved in polyomavirus-induced tumorigenesis.
Qian
W
W
Microbiology and Tumor Biology Center (MTC), Karolinska Institute, Stockholm, Sweden.
Kashuba
E
E
Magnusson
K P
KP
Pokrovskaja
K
K
Okan
I
I
Klein
G
G
Wiman
K G
KG
D000818:Animals; D002455:Cell Division; D051379:Mice; D017354:Point Mutation; D011120:Polyomavirus / Q000302:isolation & purification*; D027601:Polyomavirus Infections / Q000235:genetics*; D012513:Sarcoma, Experimental / Q000235:genetics* / Q000473:pathology / Q000821:virology; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014412:Tumor Virus Infections / Q000235:genetics*
D016159:Tumor Suppressor Protein p53