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Transformation by the simian virus 40 T antigen is regulated by IGF-I receptor and IRS-1 signaling

T DeAngelis1, J Chen, A Wu

  • 1Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Oncogene
|September 20, 2005
PubMed

Insights

Simian Virus 40 T antigen transformation requires insulin receptor substrate-1 (IRS-1) signaling. Active IRS-1, phosphorylated on tyrosines, is essential for T antigen to transform cells, highlighting the role of IRS-1/PI3K pathway in viral oncogenesis.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Virology

Background:

  • Simian Virus 40 T antigen (T antigen) transformation of mouse embryo fibroblasts (MEFs) is dependent on the type 1 insulin-like growth factor receptor (IGF-IR).
  • The precise mechanisms by which IGF-IR signaling influences T antigen's transforming activity remain incompletely understood.

Purpose of the Study:

  • To elucidate the role of insulin receptor substrate-1 (IRS-1) and downstream signaling pathways in mediating the transforming activity of Simian Virus 40 T antigen.
  • To investigate how IRS-1 phosphorylation status affects T antigen-induced cellular transformation.

Main Methods:

  • Utilized mouse embryo fibroblasts (MEFs) and 32D myeloid cells, assessing T antigen transformation.
  • Employed genetic manipulation to express wild-type or mutated IRS-1, and a constitutively active PI3K subunit.
  • Analyzed tyrosine and serine phosphorylation of IRS-1.

Main Results:

  • T antigen transformation necessitates IRS-1 that is phosphorylated on tyrosines; inactive or non-expressed IRS-1 prevents transformation.
  • Restoration of wild-type IRS-1 expression rescued T antigen's transforming ability in IRS-1-deficient cells.
  • A constitutively active PI3K subunit bypassed the requirement for serine-phosphorylated IRS-1, indicating PI3K activation is crucial.

Conclusions:

  • The IRS-1/PI3K signaling pathway is a critical regulator of Simian Virus 40 T antigen-mediated transformation.
  • The requirement for tyrosyl-phosphorylated IRS-1 explains why T antigen fails to transform cells lacking IGF-IR.

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