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International Immunology Advance Access published online on March 28, 2008
International Immunology, doi:10.1093/intimm/dxn024
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

KLF4 is a FOXO target gene that suppresses B cell proliferation

Isharat Yusuf1,5, Michael G. Kharas1, Jing Chen1, Raechel Q. Peralta1, Autumn Maruniak1, Pratibha Sareen1, Vincent W. Yang2, Klaus H. Kaestner3 and David A. Fruman1,4

1 Department of Molecular Biology and Biochemistry, University of California–Irvine, Irvine, CA, USA
2 Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA
3 Department of Genetics, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
4 Center for Immunology, University of California–Irvine, Irvine, CA, USA
5 Present address: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA

Correspondence to: Correspondence to: D. A. Fruman; E-mail: dfruman{at}uci.edu

Lymphocytes circulate in a quiescent (G0) state until they encounter specific antigens. In T cells, quiescence is programed by transcription factors of the forkhead box O (FOXO) and Krüppel-like factor (KLF) families. However, the transcription factors that regulate B cell quiescence are not known. KLF4 is a candidate tumor suppressor gene in B lymphocytes, and thus a likely candidate for regulating B cell homeostasis. Here, we show that RNA and protein expression of murine KLF4 decreases following B cell activation. Forced expression of KLF4 in proliferating B cell blasts causes a G1 cell cycle arrest. This effect requires the DNA binding and transactivation domains of KLF4 and correlates with changes in the expression of known KLF target genes. We present evidence that Klf4 is a target gene for FOXO transcription factors, which also suppress B cell proliferation. To determine the effect of KLF4 loss-of-function, we generated mice with B cell-specific deletion of the Klf4 gene. These mice exhibited normal B cell development and function with no evidence of a lowered activation threshold. Collectively, our findings indicate that KLF4 has growth-suppressive properties in B cells but might be redundant with other members of the KLF family in maintaining B cell quiescence.

Keywords: B lymphocyte, quiescence, transcription factor, tumor suppressor

Transmitting editor: S. M. Hedrick

Received 25 July 2007, accepted 13 February 2008.


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