Induction and bypass of p53 during productive infection by polyomavirus.
Lytic infection by polyomavirus leads to elevated levels of p53 and induction of p53 target genes p21Cip1/WAF1 (p21) and BAX. This is seen both in polyomavirus-infected primary mouse cell cultures and in kidney tissue of infected mice. Stabilization of p53 and induction of a p53 response are accompanied by phosphorylation of p53 on serine 18, mimicking a DNA damage response. Stabilization of p53 does not depend on p19Arf interaction with mdm2. Cells infected by a mutant virus defective in binding pRb and in inducing G(1)-to-S progression show a greatly diminished p53 response. However, cells infected by wild-type virus and blocked from entering S phase by addition of mimosine still show a p53 response. These results suggest a role of E2F target genes in inducing a p53 response. Polyomavirus large T antigen coprecipitates with p53 phosphorylated on serine 18 and also with p21Cip1/WAF1. Implications of these and other findings on possible mechanisms of induction and override of p53 functions during productive infection by polyomavirus are discussed.
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Dilip
D
Dey
Jean
J
Dahl
Sayeon
S
Cho
Thomas L
TL
Benjamin
D000818:Animals; D000831:Animals, Newborn; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D002460:Cell Line; D004279:DNA, Viral / Q000378:metabolism; D007668:Kidney / Q000821:virology; D051379:Mice; D010766:Phosphorylation; D011120:Polyomavirus / Q000472:pathogenicity*; D027601:Polyomavirus Infections / Q000821:virology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014412:Tumor Virus Infections / Q000821:virology*; D014774:Virulence
D000952:Antigens, Polyomavirus Transforming; D004279:DNA, Viral; D016159:Tumor Suppressor Protein p53