Phosphatidylinositol 3-kinase is essential for the proliferation of lymphoblastoid cells.
B-cell lymphoma, which is increasing world wide, includes such varied conditions as post-transplant lymphoproliferative disease (PTLD) and Burkitt's lymphoma. This study has characterized a role for the signalling molecule phosphatidylinositol 3-kinase, PI3K, in the regulation of growth and survival of immortalized B-lymphocytes. Burkitt's lymphoma cells die rapidly following inhibition of PI3K with LY294002, a chemical inhibitor. Furthermore, Epstein-Barr virus (EBV) immortalized B-cells, lymphoblastoid cell lines, which are a model of PTLD, do not die but are growth inhibited. This growth inhibition is due to an accumulation at G1 phase of the cell cycle and is paralleled by a loss of E2F transcriptional activity, which is essential for cell cycle entry. An active form of PI3K promotes E2F transcriptional activity in lymphoblastoid cell lines. Treatment of LCL with LY294002 causes a reduction of the expression of both cyclin D2 and cyclin D3, two key cyclins required for cell cycle progression but does not affect the expression of the EBV latent genes, EBNA2A or LMP-1. LY294002 also causes an increase in p27kip1, a cyclin dependent kinase inhibitor and results in the dephosphorylation of members of the pocket protein family. These data describe a mechanism by which PI3K plays a role in B-lymphocyte growth and suggests that a pathway from PI3K to D-type cyclin expression may provide diagnostic or treatment opportunities.
Brennan
Paul
P
Section of Infection and Immunity, Tenovus Building, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XX Wales, UK. brennanp@cf.ac.uk
Mehl
Anja M
AM
Jones
Matthew
M
Rowe
Martin
M
D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000201:enzymology* / Q000473:pathology*; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018797:Cell Cycle Proteins; D002867:Chromones; D056741:Cyclin D; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014157:Transcription Factors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one