Overexpression of p101 activates PI3Kgamma signaling in T cells and contributes to cell survival

Oncogene. 2007 Oct 25;26(49):7049-57. doi: 10.1038/sj.onc.1210504. Epub 2007 May 7.

Abstract

p101, the regulatory subunit of phosphatidylinositol-3-kinase-gamma (PI3Kgamma), was recently reported as a common site of retroviral insertion in T-cell lymphomas induced in mice by MoFe2-MuLV, a unique recombinant gammaretrovirus. The common interruption of p101 by retroviral integration suggests that the locus encodes an oncogene whose altered expression is related to the induction of T-cell malignancy. To examine a possible role in the malignant process, p101 was overexpressed in human T-cell lines Molt-4 and Jurkat. Transient overexpression of p101 induced apoptosis in recipient cells; however, stable expression could be established in cells that expressed moderate levels of p101. Constitutive p101 overexpression in those cells conferred significant protection against ultraviolet-induced apoptosis. Protection against apoptotic induction was attributed to p101-mediated activation of the Akt pathway. Constitutive overexpression of p101 enhanced the activity of p110gamma and further sensitized it to activation upon stimulation of G protein-coupled receptor. These findings are the first to implicate altered expression of p101 in malignancy, specifically in T-cell lymphoma. The findings further provide insight into the regulation of p110gamma, indicating that the stoichiometry of p110gamma and p101 are important in regulating PI3Kgamma signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology*
  • Apoptosis / radiation effects
  • Bacterial Proteins / genetics
  • Cell Survival / physiology*
  • Cell Survival / radiation effects
  • Class Ib Phosphatidylinositol 3-Kinase
  • Flow Cytometry
  • Humans
  • Immunoblotting
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Jurkat Cells / metabolism
  • Jurkat Cells / pathology
  • Luminescent Proteins / genetics
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / pathology
  • T-Lymphocytes / radiation effects
  • Ultraviolet Rays

Substances

  • Bacterial Proteins
  • Isoenzymes
  • Luminescent Proteins
  • yellow fluorescent protein, Bacteria
  • Phosphatidylinositol 3-Kinases
  • Class Ib Phosphatidylinositol 3-Kinase
  • PIK3CG protein, human
  • Pik3cg protein, mouse
  • Proto-Oncogene Proteins c-akt