KLF4 is a FOXO target gene that suppresses B cell proliferation.
Lymphocytes circulate in a quiescent (G(0)) state until they encounter specific antigens. In T cells, quiescence is programmed 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 G(1) 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.
Yusuf
Isharat
I
Department of Molecular Biology and Biochemistry, University of California-Irvine, Irvine, CA, USA.
Kharas
Michael G
MG
Chen
Jing
J
Peralta
Raechel Q
RQ
Maruniak
Autumn
A
Sareen
Pratibha
P
Yang
Vincent W
VW
Kaestner
Klaus H
KH
Fruman
David A
DA
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002453:Cell Cycle; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000502:physiology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1
D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D014157:Transcription Factors; C000715468:Klf4 protein, mouse; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1