Overexpression of p101 activates PI3Kgamma signaling in T cells and contributes to cell survival.
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.
Johnson
C
C
Department of Microbiology and Immunology and Tulane Cancer Center, Tulane University Health Sciences Center, New Orleans, LA, USA.
Marriott
S J
SJ
Levy
L S
LS
D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects; D001426:Bacterial Proteins / Q000235:genetics; D002470:Cell Survival / Q000502:physiology* / Q000528:radiation effects; D058544:Class Ib Phosphatidylinositol 3-Kinase; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D019169:Jurkat Cells / Q000378:metabolism / Q000473:pathology; D008164:Luminescent Proteins / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D014466:Ultraviolet Rays
D001426:Bacterial Proteins; D007527:Isoenzymes; D008164:Luminescent Proteins; C054562:yellow fluorescent protein, Bacteria; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse; D051057:Proto-Oncogene Proteins c-akt