title: Ikaros limits follicular B cell activation by regulating B cell receptor signaling pathways.
abstract: The Ikaros transcription factor is essential for early B cell development, but its effect on mature B cells is debated. We show that Ikaros is required to limit the response of naive splenic B cells to B cell receptor signals. Ikaros deficient follicular B cells grow larger and enter cell cycle faster after anti-IgM stimulation. Unstimulated mutant B cells show deregulation of positive and negative regulators of signal transduction at the mRNA level, and constitutive phosphorylation of ERK, p38, SYK, BTK, AKT and LYN. Stimulation results in enhanced and prolonged ERK and p38 phosphorylation, followed by hyper-proliferation. Pharmacological inhibition of ERK and p38 abrogates the increased proliferative response of Ikaros deficient cells. These results suggest that Ikaros functions as a negative regulator of follicular B cell activation.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Beate
authors.initials: B
authors.lastname: Heizmann
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France; David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
authors.forename: MacLean
authors.initials: M
authors.lastname: Sellars
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France; Institute for Medical Engineering and Science at MIT, Cambridge, MA 02139, USA.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Macias-Garcia
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France. Electronic address: scpk@igbmc.fr.
authors.forename: Susan
authors.initials: S
authors.lastname: Chan
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France; Faculté de Médecine, Université de Strasbourg, Strasbourg, France. Electronic address: scpk@igbmc.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Kastner
mesh_terms: D000818:Animals; D001402:B-Lymphocytes; D049109:Cell Proliferation / Q000502:physiology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D051740:Ikaros Transcription Factor / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013154:Spleen / Q000166:cytology*
chemical_list: D011947:Receptors, Antigen, B-Cell; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor
keywords: Activation; B cell receptor; B cell signaling; Ikaros; MAPK; Transcription factor; Transcriptional program