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Published online
doi:10.1083/jcb.200704173
The Journal of Cell Biology, Vol. 179, No. 4, 717-731
The Rockefeller University Press, 0021-9525 $30.00
© Habib et al.
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Article

Myc stimulates B lymphocyte differentiation and amplifies calcium signaling



Tania Habib1, Heon Park1, Mark Tsang1, Ignacio Moreno de Alborán2, Andrea Nicks1, Leslie Wilson1, Paul S. Knoepfler4, Sarah Andrews3, David J. Rawlings3, Robert N. Eisenman4, and Brian M. Iritani1,4

1 Department of Comparative Medicine, University of Washington, Seattle, WA 98195
2 Department of Immunology and Oncology, Centro Nacional de Biotecnología, Universidad Autonoma de Madrid, Cantoblanco, Madrid 28049, Spain
3 Immunology Clinic, Children's Hospital and Regional Medical Center, Seattle, WA 98104
4 Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109

Correspondence to Brian M. Iritani: biritani{at}u.washington.edu

Deregulated expression of the Myc family of transcription factors (c-, N-, and L-myc) contributes to the development of many cancers by a mechanism believed to involve the stimulation of cell proliferation and inhibition of differentiation. However, using B cell–specific c-/N-myc double-knockout mice and Eµ-myc transgenic mice bred onto genetic backgrounds (recombinase-activating gene 2–/– and Btk–/– Tec–/–) whereby B cell development is arrested, we show that Myc is necessary to stimulate both proliferation and differentiation in primary B cells. Moreover, Myc expression results in sustained increases in intracellular Ca2+ ([Ca2+]i), which is required for Myc to stimulate B cell proliferation and differentiation. The increase in [Ca2+]i correlates with constitutive nuclear factor of activated T cells (NFAT) nuclear translocation, reduced Ca2+ efflux, and decreased expression of the plasma membrane Ca2+–adenosine triphosphatase (PMCA) efflux pump. Our findings demonstrate a revised model whereby Myc promotes both proliferation and differentiation, in part by a remarkable mechanism whereby Myc amplifies Ca2+ signals, thereby enabling the concurrent expression of Myc- and Ca2+-regulated target genes.

Abbreviations used in this paper: BCR, B cell receptor; BM, bone marrow; CFA, complete Freund's adjuvant; CFSE, 5-carboxyfluorescein diacetate succinimidyl ester; ChIP, chromatin immunoprecipitation; Cn, calcineurin; CsA, cyclosporine A; GL, germline; HC, heavy chain; HSA, heat-stable antigen; IRES, internal ribosomal entry site; KLH, keyhole limpet hemocyanin; LC, light chain; MSCV, murine stem cell virus; MZ, marginal zone; NFAT, nuclear factor of activated T cells; NF-{kappa}B, nuclear factor {kappa}B; PE, phycoerythrin; PI3K, phosphatidylinositol 3-kinase; PMCA, plasma membrane Ca2+-ATPase; PTK, protein tyrosine kinase; qPCR, quantitative PCR; RAG2, recombinase-activating gene 2; SERCA, sarcoplasmic ER Ca2+ ATPase; Tg, transgene; Wt, wild type.


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