Expression of a mutated form of the p85alpha regulatory subunit of phosphatidylinositol 3-kinase in a Hodgkin's lymphoma-derived cell line (CO).
Phosphatidylinositol (PI) 3-kinase plays an important role in a variety of biological processes, including proliferation and apoptosis. PI3-kinase is a heterodimer consisting of an 85 kDa adapter protein (p85) containing one SH3 domain and two SH2 domains and a 110 kDa catalytic subunit (p110). Recently an oncogenic form of p85 named p65-PI3K lacking the C-terminal SH2 domain has been cloned from an irradiation-induced murine thymic lymphoma and transgenic mice expressing p65-PI3K in T lymphocytes develop a lymphoproliferative disorder. Here we describe the cloning of a C-terminal truncated form of p85 expressed in a human lymphoma cell line (CO) with a T cell phenotype derived from a patient with Hodgkin's disease. As a result of a frame-shift mutation at amino acid 636, p76 is lacking most of the C-terminal SH2 domain, but contains the inter-SH2 domain and is associated with an active form of PI3-kinase. A PI3-kinase-dependent constitutive activation of Akt was detected in CO cells which was only partially reduced after serum starvation. Treatment of CO cells with the PI3-kinase inhibitor wortmannin resulted in a concentration-dependent inhibition of cell proliferation associated with an increased number of apoptotic cells. This is the first detection of a mutated form of the p85 subunit of PI3-kinase in human hematopoietic cells further underlining a potential role of PI3-kinase/Akt signaling in human leukemogenesis.
Jücker
M
M
Institut für Medizinische Biochemie und Molekularbiologie, Abteilung für Zelluläre Signaltransduktion, Universitätsklinikum Hamburg-Eppendorf, Universität Hamburg, Martinistrasse 52, 20246 Hamburg, Germany.
Südel
K
K
Horn
S
S
Sickel
M
M
Wegner
W
W
Fiedler
W
W
Feldman
R A
RA
D017209:Apoptosis / Q000502:physiology; D003001:Cloning, Molecular; D019281:Dimerization; D004789:Enzyme Activation; D016368:Frameshift Mutation; D006689:Hodgkin Disease / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000201:enzymology / Q000473:pathology; D014407:Tumor Cells, Cultured; D018909:src Homology Domains / Q000235:genetics
D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C494918:AKT1 protein, human