The SV40 large T antigen-p53 complexes bind and activate the insulin-like growth factor-I promoter stimulating cell growth.
Inactivation of cellular p53 is a crucial step in carcinogenesis. Accordingly, p53 is inactivated in most human cancers by different mechanisms. In cells infected with DNA tumor viruses, p53 is bound to the viral tumor antigens (Tag). The current "dogma" views the Tag-p53 complexes as a way of sequestering and inactivating p53. Using primary human cells and SV40-transformed human cells, we show that in addition to inactivating p53 tumor suppressor activities, the Tag-p53 complex has growth stimulatory activities that are required for malignant cell growth. We found that in human cells, Tag-p53 complexes regulate transcription of the insulin-like growth factor I (IGF-I) gene by binding to the IGF-I promoter together with pRb and p300. Depletion of p53 leads to structural rearrangements of this multiprotein complex, resulting in IGF-I promoter transcriptional repression and growth arrest. Our data provide a novel mechanistic and biological interpretation of the p53-Tag complexes and of DNA tumor virus transformation in general. In the model we propose, p53 is not a passive inactive partner of Tag. Instead the p53-Tag complex promotes malignant cell growth through its ability to activate the IGF-I signaling pathway.
Bocchetta
Maurizio
M
Department of Pathology and Oncology Institute, Loyola University Chicago, Cancer Center, Maywood, Illinois 60153, USA. mbocche@lumc.edu
Eliasz
Sandra
S
De Marco
Melissa Arakelian
MA
Rudzinski
Jennifer
J
Zhang
Lei
L
Carbone
Michele
M
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism*; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D014161:Transduction, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000952:Antigens, Polyomavirus Transforming; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D011994:Recombinant Proteins; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1