Myc stimulates B lymphocyte differentiation and amplifies calcium signaling.
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 E(mu)-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.
Habib
Tania
T
Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.
Park
Heon
H
Tsang
Mark
M
de Alborán
Ignacio Moreno
IM
Nicks
Andrea
A
Wilson
Leslie
L
Knoepfler
Paul S
PS
Andrews
Sarah
S
Rawlings
David J
DJ
Eisenman
Robert N
RN
Iritani
Brian M
BM
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D005347:Fibroblasts / Q000378:metabolism; D017930:Genes, Reporter; D016259:Genes, myc; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000378:metabolism; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*
D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D008156:Luciferases; D053499:Plasma Membrane Calcium-Transporting ATPases; D002118:Calcium