PI3K/Akt signaling pathway regulates c-Myc via NFkB and GSK3b in mouse iMyc-Em B lymphoma cells Free

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MYC-activating chromosomal t(8;14)(q24;q32) translocations are widely believed to be the initiating oncogenic events in the pathogenesis of the human post-germinal center non-Hodgkin lymphoma, Burkitt lymphoma. To mimic these translocations in transgenic mice, we recently generated three different “iMyc” gene-insertion strains, including iMyc^Eμ, that contain mouse Myc in three different sites of the immunoglobulin heavy-chain gene cluster. Using the B cell lymphoma-derived cell line iMycEμ-1 as a model system, we demonstrated here that inhibition of phosphatidylinositol 3-kinase (PI3K) by the small drug LY294002, or by a dominant negative form of p85, resulted in apoptosis of the lymphoma cells. LY294002 abolished I kappa B alpha (IkBα) kinase activation following hypophosphorylation of the NF-kappaB component, p65. This change coincided with a drop of Myc, which is degraded in the proteasome in a PI3K/Akt-dependent manner via phosphorylation of glycogen synthase kinase (GSK)-3β. Our results suggest that the PI3K/Akt pathway plays an important role in Myc regulation, either through Rel/NFkB-dependent transcription of the inserted iMyc^Eμ gene or the post-transcriptional regulation of Myc protein levels. The iMyc^Eμ mice may provide a good tool for the design and testing of new approaches to treat and prevent MYC-dependent B cell and plasma cell neoplasms in human beings.