Transformation by the simian virus 40 T antigen is regulated by IGF-I receptor and IRS-1 signaling.
Previous work has shown that the Simian Virus 40 T antigen (T antigen) cannot transform mouse embryo fibroblasts (MEFs) that do not express the type 1 insulin-like growth factor receptor (IGF-IR). We have now investigated the mechanism(s) by which the transforming activity of T antigen is affected by IGF-IR signaling. We demonstrate that transformation by T antigen of MEFs and several other cell lines requires an insulin receptor substrate-1 (IRS-1) phosphorylated on tyrosines. If IRS-1 is not expressed, or is serine phosphorylated or otherwise inactive, T antigen fails to transform cells in culture. For instance, while T antigen cannot transform 32D myeloid cells (that do not express IRS-1), its transforming activity is restored by the expression of a wild-type IRS-1, but not of an IRS-1 mutated at the PI3K binding sites. The importance of IRS-1 activation of PI3K in T-antigen transformation is supported by the finding that a constitutively activated p110 subunit of PI3K, a target of IRS-1, overcomes the inability of T antigen to transform MEFs with a serine phosphorylated IRS-1. Taken together, these results indicate that the IRS-1/PI3K signaling is one of the mechanisms regulating transformation by the SV40 T antigen. We propose that the requirement for a tyrosyl-phosphorylated IRS-1 provides a mechanism to explain the failure of T antigen to transform MEFs with deleted IGF-IR genes.
DeAngelis
T
T
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Chen
J
J
Wu
A
A
Prisco
M
M
Baserga
R
R
D000362:Agar / Q000737:chemistry; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000737:chemistry* / Q000378:metabolism; D000957:Antigens, Viral, Tumor / Q000737:chemistry; D001665:Binding Sites; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism; D002460:Cell Line; D002461:Cell Line, Transformed; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism*; D017353:Gene Deletion; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D035463:Pol1 Transcription Initiation Complex Proteins / Q000378:metabolism; D012313:RNA / Q000737:chemistry; D012335:RNA, Ribosomal / Q000737:chemistry; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D012270:Ribosomes / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry
D000952:Antigens, Polyomavirus Transforming; D000957:Antigens, Viral, Tumor; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D035463:Pol1 Transcription Initiation Complex Proteins; D012335:RNA, Ribosomal; C063844:transcription factor UBF; D014443:Tyrosine; D012694:Serine; D012313:RNA; D000362:Agar; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1