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Regulation of p27^Kip1 Accumulation in Murine B-Lymphoma Cells: Role of c-Myc and Calcium¹

Dubravka Donjerkovi, Liying Zhang and David W. Scott²

Department of Immunology, Holland Laboratory for the Biomedical Sciences, American Red Cross, Rockville, Maryland 20855 [D. D., L. Z., D. W. S.], and Molecular and Cellular Oncology Program, George Washington University, Washington, DC 20037 [D. D., D. W. S.]

Abstract

IgM cross-linking induces G₁ arrest and apoptosis in murine B-lymphoma cells. It prevents pRb phosphorylation by decreasing cyclin-dependent kinase 2 activity via the up-regulation of cyclin kinase inhibitor p27^Kip1. Anti-IgM also causes an increase in cytosolic free calcium and a loss of c-myc mRNA and protein. This down-regulation of c-Myc is prevented by CD40L, which rescues cells from anti-IgM-induced apoptosis. In this study, we addressed the mechanism(s) of anti-IgM-induced p27^Kip1 accumulation. We examined effects of early events in B-cell receptor-mediated signaling, c-Myc down-regulation, and an increase in free calcium on p27^Kip1. Down-regulation of c-myc alone had no effect on p27^Kip1; neither did an increase in free calcium alone. Together, these two events led to p27^Kip1 induction, growth arrest, and apoptosis. CD40L, the calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester, and cyclosporin A all prevented anti-IgM-induced p27^Kip1 accumulation, suggesting that both the decrease in c-Myc expression and an increase in free calcium are necessary for p27^Kip1 up-regulation.

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