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

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 p85α subunit of phosphatidylinositol 3‐kinase (PI3K) or other components of the B cell signalosome, p110δ‐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 p85α‐null and p110δ‐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 p85α‐null and p110δ‐null B cells, and our data suggests that cross‐talk exists between the PI3K and JNK pathways.