Wild-type p53 enhances efficiency of simian virus 40 large-T-antigen-induced cellular transformation.
Abortive infection of BALB/c mouse embryo fibroblasts differing in p53 gene status (p53(+/+) versus p53(-/)(-)) with simian virus 40 (SV40) revealed a quantitatively and qualitatively decreased transformation efficiency in p53(-/-) cells compared to p53(+/+) cells, suggesting a supportive effect of wild-type (wt) p53 in the SV40 transformation process. SV40 transformation efficiency also was low in immortalized p53(-/-) BALB/c 10-1 cells but could be restored to approximately the level in immortalized p53(+/+) BALB/c 3T3 cells by reconstituting wt p53, but not mutant p53 (mutp53), expression. Stable expression of large T antigen (LT) in p53(+/+) 3T3 cells resulted in full transformation, while LT expression in p53(-/-) 10-1 cells could not promote growth in suspension or in soft agar to a significant extent. The helper effect of wt p53 is mediated by its cooperation with LT and resides in the p53 N terminus, as an N-terminally truncated p53 (DeltaNp53) could not rescue the p53-null phenotype. The p53 N terminus serves as a scaffold for recruiting transcriptional regulators like p300/CBP and Mdm2 into the LT-p53 complex. Consequently, LT affected global and specific gene expression in p53(+/+) cells significantly more than in p53(-/-) cells. Our data suggest that recruitment of transcriptional regulators into the LT-p53 complex may help to modify cellular gene expression in response to the needs of cellular transformation.
Hermannstädter
Andrea
A
Heinrich-Pette-Institute for Experimental Virology and Immunology Martinistr. 52, D-20251 Hamburg, Germany.
Ziegler
Christine
C
Kühl
Marion
M
Deppert
Wolfgang
W
Tolstonog
Genrich V
GV
D016475:3T3 Cells; D000818:Animals; D000957:Antigens, Viral, Tumor / Q000096:biosynthesis*; D019556:COS Cells; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral / Q000235:genetics*; D002522:Chlorocebus aethiops; D005347:Fibroblasts / Q000821:virology; D019084:Fluorescent Antibody Technique, Indirect; D015967:Gene Expression Regulation, Viral; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D013539:Simian virus 40 / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000957:Antigens, Viral, Tumor; D016159:Tumor Suppressor Protein p53