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• W2783403078 abstract "BCR-ligation in B lymphocytes results in differential biological responses according to the maturational stage of the cell. Thus, while mature B lymphocytes become activated and proliferate in response to antigen receptor crosslinking, immature B lymphocytes become unresponsive or undergo apoptosis. Although these biological responses to antigen are well reported, the signalling pathways activated in each scenario are still poorly defined. In particular, the signalling cascades that result in the apoptosis of immature B lymphocytes which recognise self-antigen are still unclear. Recent studies within our group have highlighted the phospholipase, CPLA2, as a possible transducer of apoptotic signals following BCR-ligation (53) in WEHI-231 cells. Additionally, CD40 co-stimulation has been shown to rescue immature B lymphocyte from BCR-mediated apoptosis. We were therefore interested in investigating the signalling pathways linking the BCR to cPLA2 activation and the mechanisms utilised by CD40 co-stimulation in the reversal of BCR-mediated apoptosis. Initial studies examined the activation of the MAPKinase family of enzymes as these protein kinases, along with Ca2+, have been implicated in the activation of CPLA2. Our studies indicated that BCR-ligation induced the activation of a short, transient, ERK-MAPKinase signal, but not p38 MAPKinase or JNK. Additional studies have shown that inhibition of this ERK-MAPKinase signal by pharmacological means reduces BCR-induced apoptosis and cPLA2 activation. Interestingly, CD40 costimulation was shown to uncouple the BCR from ERK-MAPKinase activation, suggesting the prevention of cPLA2 activation may account for the anti-apoptotic properties of CD40 co-stimulation. BCR-induced apoptosis of WEHI-231 cells is known to occur approximately 24-48 hours post receptor ligation. We therefore examined the activity of ERK- MAPKinase over these time periods. Interestingly, untreated WEHI-231 cells were shown to exhibit a basal cycling, ERK-MAPKinase activity, suggesting this protein was involved in the normal proliferation of these cells. BCR-ligation was shown to abolish this signal after approximately 2-4hsuggesting that BCR-induced growth arrest involves the down-regulation of this cyclic ERK-MAPKinase activity. Additionally, CD40 co-stimulation was shown to restore this proliferative ERK-MAPKinase signal. Inhibitor studies corroborated this proposal that these late, cycling ERK-MAPKinase signals contribute to basal and CD40-rescued growth and proliferation of WEHI-231 cells. In summary, these results suggest differential roles for ERK-MAPKinase in regulating WEHI-231 cell fate. Firstly, an early, BCR-stimulated apoptotic signal, and secondly, a long-term proliferative signal. They also suggest that the induction of growth arrest and apoptosis in WEHI-231 cells result from the activation of distinct signalling pathways. We therefore investigated possible mechanisms involved in both the suppression, and re-establishment, of proliferative ERK-MAPKinase activity by BCR- ligation and CD40 co-stimulation respectively. Firstly, we examined the role of PI(3)K which is known to be involved in the induction of survival signals and ERK- MAPKinase activation in other cell systems. Our results suggested that PI(3)K mediated PtdIns(3,4,5)P3 generation does not play a role in CD40-mediated rescue from BCR-induced growth arrest. These results were corroborated by the inability to detect activity of the anti-apoptotic protein, Akt, following CD40 co-stimulation. Inhibitor studies did however indicate that PI(3)K activity plays a role in the basal proliferation of WEHI-231 cells. However, PtdIns(3,4,5)P3 generation, unlike basal ERK- MAPKinase, was not found to be cyclic in nature. These findings do not rule out a role for the involvement of other phosphatidylinositol species generated by PI(3)K activity, including PtdIns(3,4)P2 which is known to activate ERK-MAPKinase. (Abstract shortened by ProQuest.)." @default.
• W2783403078 created "2018-01-26" @default.
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• W2783403078 date "2000-01-01" @default.
• W2783403078 modified "2023-09-24" @default.
• W2783403078 title "Differential roles of ERK-MAPKinase in WEHI-231 cell apoptosis and growth" @default.
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