title: Myc stimulates B lymphocyte differentiation and amplifies calcium signaling.
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 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.
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Tania
authors.initials: T
authors.lastname: Habib
authors.forename: Heon
authors.initials: H
authors.lastname: Park
authors.forename: Mark
authors.initials: M
authors.lastname: Tsang
authors.forename: Ignacio Moreno
authors.initials: IM
authors.lastname: de Alborán
authors.forename: Andrea
authors.initials: A
authors.lastname: Nicks
authors.forename: Leslie
authors.initials: L
authors.lastname: Wilson
authors.forename: Paul S
authors.initials: PS
authors.lastname: Knoepfler
authors.forename: Sarah
authors.initials: S
authors.lastname: Andrews
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawlings
authors.forename: Robert N
authors.initials: RN
authors.lastname: Eisenman
authors.forename: Brian M
authors.initials: BM
authors.lastname: Iritani
mesh_terms: 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*
chemical_list: D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D008156:Luciferases; D053499:Plasma Membrane Calcium-Transporting ATPases; D002118:Calcium