Myc stimulates B lymphocyte differentiation and amplifies calcium signaling

Tania Habib, Heon Park, Mark Tsang, Ignacio Moreno De Alborán, Andrea Nicks, Leslie Wilson, Paul S Knoepfler, Sarah Andrews, David J. Rawlings, Robert N. Eisenman, Brian M. Iritani

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

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+ ([Ca 2+]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.

Original languageEnglish (US)
Pages (from-to)717-731
Number of pages15
JournalJournal of Cell Biology
Volume179
Issue number4
DOIs
StatePublished - Nov 19 2007
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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    Habib, T., Park, H., Tsang, M., De Alborán, I. M., Nicks, A., Wilson, L., Knoepfler, P. S., Andrews, S., Rawlings, D. J., Eisenman, R. N., & Iritani, B. M. (2007). Myc stimulates B lymphocyte differentiation and amplifies calcium signaling. Journal of Cell Biology, 179(4), 717-731. https://doi.org/10.1083/jcb.200704173