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J. Biol. Chem., Vol. 278, Issue 6, 4358-4367, February 7, 2003

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Cross-linking of Surface IgM in the Burkitt's Lymphoma Cell Line ST486 Provides Protection against Arsenite- and Stress-induced Apoptosis That Is Mediated by ERK and Phosphoinositide 3-Kinase Signaling Pathways^*

Donna E. Muscarella and Stephen E. Bloom

From the Department of Microbiology and Immunology, Cornell University, Ithaca, New York 14853

The ST486 cell line, derived from a human Burkitt's lymphoma, is a model for antigen-induced clonal deletion in germinal center B-lymphocytes, with apoptosis induced upon cross-linking of surface IgM. Moreover, this cell line is highly sensitive to the induction of apoptosis by many chemicals, including sodium arsenite, a significant environmental contaminant with immunotoxic activity. In contrast to arsenite and other chemicals, surface IgM cross-linking induces apoptosis in ST486 cells with delayed kinetics. Moreover, the initial signaling events following IgM stimulation are associated with cell survival and proliferation and include activation of the extracellular-signal regulated kinase (ERK) and the phosphoinositide 3-kinase (PI3K) pathways. We examined the question of whether IgM-mediated activation of the ERK and PI3K pathways can influence the apoptotic response of ST486 cells following exposure to arsenite and selected drugs with different molecular targets, including cycloheximide, etoposide, and camptothecin, and a physical stress, hyperthermia. Our findings show that IgM-stimulated cells are significantly protected against arsenite and drug-induced apoptosis during a window of several hours after surface IgM cross-linking, as evidenced by an inhibition of cleavage of poly(ADP-ribose) polymerase and lack of morphological changes indicative of apoptosis. Significantly, surface IgM cross-linking also protects against arsenite-induced mitochondrial depolarization as well as caspase-9 cleavage. Furthermore, we demonstrate that this IgM-mediated protection requires the activation of the ERK and PI3K pathways, because inhibition of either pathway blocks the ability of antigen receptor activation to protect against apoptosis. Our study also provides evidence for p90^S6 ribosomal kinase as a point of convergence between the two signaling pathways resulting in the phosphorylation of the pro-apoptotic Bcl-2 family member Bad at serine 112. This investigation demonstrates, for the first time, that specific signals transduced by activation of the B-cell receptor protect cells at a common point of regulation in the apoptotic pathways for diverse stresses.

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