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B/Rel Are at the Divergence of CD40-Mediated Proliferation and Survival Pathways
*
Division of Immunology, Department of Medicine, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021;
Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan; and
Department of Internal Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan
CD40 receptor ligation evokes several crucial outcomes for the fate
of an activated B cell, including proliferation and survival. Although
multiple signaling molecules in the CD40 pathways have been identified,
their specific roles in regulating proliferation and maintaining cell
viability are still obscure. In this report, we demonstrate that the
activation of both phosphatidylinositol 3-kinase (PI-3K) and
NF-
B/Rel transcription factors is crucial for CD40-mediated
proliferation. Furthermore, our data indicate that PI-3K is
indispensable for CD40-mediated NF-B/Rel activation. This is
achieved via activation of AKT and the degradation of IB
.
Furthermore, we show that PI-3K activity is necessary for the
degradation of cyclin-dependent kinase inhibitor p27kip.
Therefore, both of these events comprise the mechanism by which PI-3K
controls cell proliferation. In contrast to the absolute requirement of
PI-3K and NF-B/Rel for proliferation, these signaling molecules are
only partially responsible for CD40-mediated survival, as blocking of
PI-3K activity did not lead to apoptosis of anti-CD40-treated
cells. However, the PI-3K/NF-B pathway is still required for
CD40-induced Bcl-X gene expression. Taken together, our data indicate
that multiple survival pathways are triggered via this receptor,
whereas NF-B/Rel and PI-3K are crucial for CD40-induced
proliferation.
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