Phosphatidylinositol 3-kinase is required for the transcriptional activation of cyclin D2 in BCR activated primary mouse B lymphocytes

Janet Glassford, Elena Vigorito, Inês Soeiro, Patricia A Madureira, Georgia Zoumpoulidou, Jan J Brosens, Martin Turner, Eric W-F Lam

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2748-2761
Number of pages14
JournalEuropean Journal of Immunology
Volume35
Issue number9
DOIs
Publication statusPublished - 6 Sep 2005

Keywords

  • Androstadienes/pharmacology
  • Animals
  • B-Lymphocytes/enzymology
  • Blotting, Western
  • Cell Cycle/immunology
  • Chromones/pharmacology
  • Cyclin D2
  • Cyclins/genetics
  • Lymphocyte Activation/immunology
  • Mice
  • Mice, Knockout
  • Morpholines/pharmacology
  • Phosphatidylinositol 3-Kinases/antagonists & inhibitors
  • Protein Kinase Inhibitors/pharmacology
  • RNA/chemistry
  • Receptors, Antigen, B-Cell/immunology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction/immunology
  • Transcriptional Activation
  • Wortmannin

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