KLF4 is a FOXO target gene that suppresses B cell proliferation

Department of Molecular Biology and Biochemistry, University of California-Irvine, Irvine, CA, USA.
International Immunology (Impact Factor: 2.54). 06/2008; 20(5):671-81. DOI: 10.1093/intimm/dxn024
Source: PubMed


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.

Download full-text


Available from: Vincent W Yang, Jan 03, 2014
  • Source
    • "In embryonic stem cells, induction of KLF2 by OCT4 and of KLF4 by LIF has been demonstrated, providing further evidence supporting these KLFs' function in stem cell renewal (Hall et al. 2009). KLF4 expression was suppressed by the transcription factor FOXO in B-lymphocytes (Yusuf et al. 2008) and by an inhibitor of Notch signaling in the mouse gastrointestinal tract (Zheng et al. 2009) and, conversely, was induced by Notch 1 intracellular domain in ocular surface epithelia (Zhang et al. 2013). KLF6 expression was stimulated by IGF1 in human colon cancer cell lines (Bentov et al. 2008), and the binding of carbohydrate-response-element-binding protein, a glucoseactivated transcription factor, induced KLF10 promoter activity and expression in rat hepatocytes (Iizuka et al. 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Female reproductive tract pathologies arise largely from dysregulation of estrogen and progesterone receptor signaling leading to aberrant cell proliferation, survival and differentiation. The signaling pathways orchestrated by these nuclear receptors are complex, require the participation of many nuclear proteins serving as key binding partners or targets and involve a range of paracrine and autocrine regulatory circuits. Members of the Krüppel-like family of transcription factors are ubiquitously expressed in reproductive tissues and have been increasingly implicated as critical co-regulators and integrators of steroid hormone actions. Here we explore the involvement of KLF family members in uterine pathology, describe their currently known molecular mechanisms and discuss their potential as targets for therapeutic intervention.
    Journal of Molecular Endocrinology 02/2015; 54(2). DOI:10.1530/JME-14-0310 · 3.08 Impact Factor
  • Source
    • "In the immune system, KLF4 regulates the development of monocytes, maintenance of splenic dendritic cells, and differentiation of T cells [10,13–16]. In addition, KLF4 inhibits proliferation of B cells downstream of FOXO proteins [17]. We have previously shown that in vitro TCR stimulation of CD8 + T cells leads to a rapid downregulation of the transcription factor E74-like factor 4 (ELF4) followed by suppression of KLF4, a direct target of ELF4 [9] [18]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The transcription factor Krüppel-like factor 4 (KLF4) can activate or repress gene expression in a cell-context dependent manner. We have previously shown that KLF4 inhibits the proliferation of naïve CD8(+) T cells in vitro downstream of the transcription factor ELF4. In this work, we describe a novel role of KLF4 in the differentiation of CD8(+) T cells upon infection. Loss of KLF4 had minimal effect on thymic T cell development and distribution of mature T cells in the spleen, blood, and lymph nodes. KLF4-deficient naïve CD8(+) T cells also displayed normal homeostatic proliferation upon adoptive transfer into lymphopenic hosts. However, activation of KLF4-deficient naïve CD8(+) T cells by in vitro TCR crosslink and co-stimulation resulted in increased proliferation. Furthermore, naïve KLF4-deficient OT-I CD8(+) T cells generated increased numbers of functional memory CD8(+) T cells compared to wild type OT-I CD8(+) T cells co-injected in the same recipient in both primary and recall responses to Listeria monocytogenes-OVA. Collectively, our data demonstrate that KLF4 regulates differentiation of functional memory CD8(+) T cells while sparing development and homeostasis of naïve CD8(+) T cells.
    Immunology letters 09/2013; 156(1-2). DOI:10.1016/j.imlet.2013.09.008 · 2.51 Impact Factor
  • Source
    • "The negative regulation of IL-17 and IL-22 expression represents a novel function of KLF2. KLFs are a large family of zinc-finger transcription factors (Kaczynski et al., 2003; van Vliet et al., 2006); they play important roles in cellular differentiation and homeostasis (Kuo et al., 1997b; Wani et al., 1999; Atkins and Jain, 2007; Jiang et al., 2008; Yusuf et al., 2008; Yamada et al., 2009). KLF2 specifically has been reported to maintain naive T cell quiescence and survival in the mouse (Anderson et al., 1995; Kuo et al., 1997a,b; Wani et al., 1998, 1999; Kuo and Leiden, 1999; Buckley et al., 2001; Di Santo, 2001; Jiang et al., 2008; Yamada et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Human memory T cells (T(M) cells) that produce IL-17 or IL-22 are currently defined as Th17 or Th22 cells, respectively. These T cell lineages are almost exclusively CCR6(+) and are important mediators of chronic inflammation and autoimmunity. However, little is known about the mechanisms controlling IL-17/IL-22 expression in memory Th17/Th22 subsets. We show that common γ chain (γc)-using cytokines, namely IL-2, IL-7, and IL-15, potently induce Th17-signature cytokine expression (Il17a, Il17f, Il22, and Il26) in CCR6(+), but not CCR6(-), T(M) cells, even in CCR6(+) cells lacking IL-17 expression ex vivo. Inhibition of phosphoinositide 3-kinase (PI-3K) or Akt signaling selectively prevents Th17 cytokine induction by γc-cytokines, as does ectopic expression of the transcription factors FOXO1 or KLF2, which are repressed by PI-3K signaling. These results indicate that Th17 cytokines are tuned by PI-3K signaling in CCR6(+) T(M) cells, which may contribute to chronic or autoimmune inflammation. Furthermore, these findings suggest that ex vivo analysis of IL-17 expression may greatly underestimate the frequency and pathogenic potential of the human Th17 compartment.
    Journal of Experimental Medicine 08/2011; 208(9):1875-87. DOI:10.1084/jem.20102516 · 12.52 Impact Factor
Show more