title: Phosphatidylinositol 3-kinase is required for the transcriptional activation of cyclin D2 in BCR activated primary mouse B lymphocytes.
abstract: Induction of cyclin D2 is essential for mediating cell cycle entry in B cells activated by BCR cross-linking. In the present study we show that, like B lymphocytes lacking cyclin D2, the p85alpha subunit of phosphatidylinositol 3-kinase (PI3K) or other components of the B cell signalosome, p110delta-null B cells fail to induce cyclin D2 and enter early G1 but not S phase of the cell cycle. The inhibitors of PI3K activity, LY294002 and Wortmannin, also abrogate cyclin D2 induction by BCR cross-linking, confirming that the class IA PI3K is necessary for cyclin D2 induction in response to BCR stimulation. Furthermore, using both p85alpha-null and p110delta-null B cells and inhibitors of PI3K, this study demonstrates for the first time, that BCR cross-linking induces cyclin D2 mRNA expression via transcriptional activation of the cyclin D2 promoter and that this transcriptional activation of cyclin D2 requires PI3K activity. Moreover, we identify a region between nucleotides -1624 and -1303 of the cyclin D2 promoter containing elements responsive to anti-IgM, which are PI3K dependent. Further characterisation of signalling intermediates downstream of the BCR revealed a perturbation of MAPK signalling pathways in p85alpha-null and p110delta-null B cells, and our data suggests that cross-talk exists between the PI3K and JNK pathways.
authors.affiliation: Cancer Research-UK laboratories, Department of Cancer Medicine, MRC Cyclotron Building, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Janet
authors.initials: J
authors.lastname: Glassford
authors.forename: Elena
authors.initials: E
authors.lastname: Vigorito
authors.forename: Inês
authors.initials: I
authors.lastname: Soeiro
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Madureira
authors.forename: Georgia
authors.initials: G
authors.lastname: Zoumpoulidou
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Brosens
authors.forename: Martin
authors.initials: M
authors.lastname: Turner
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000502:physiology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000276:immunology; D002867:Chromones / Q000494:pharmacology; D058534:Class I Phosphatidylinositol 3-Kinases; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D015533:Transcriptional Activation; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002867:Chromones; D058534:Class I Phosphatidylinositol 3-Kinases; D056742:Cyclin D2; D016213:Cyclins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D012313:RNA; D011947:Receptors, Antigen, B-Cell; D000077191:Wortmannin; C486196:Ccnd2 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C421683:Pik3cd protein, mouse