The Fox Genes in the Liver: From Organogenesis to Functional Integration

William Penn University, Filadelfia, Pennsylvania, United States
Physiological Reviews (Impact Factor: 27.32). 01/2010; 90(1):1-22. DOI: 10.1152/physrev.00018.2009
Source: PubMed


Formation and function of the liver are highly controlled, essential processes. Multiple signaling pathways and transcriptional regulatory networks cooperate in this complex system. The evolutionarily conserved FOX, for Forkhead bOX, class of transcriptional regulators is critical to many aspects of liver development and function. The FOX proteins are small, mostly monomeric DNA binding factors containing the so-called winged helix DNA binding motif that distinguishes them from other classes of transcription factors. We discuss the biochemical and genetic roles of Foxa, Foxl1, Foxm1, and Foxo, as these have been shown to regulate many processes throughout the life of the organ, controlling both formation and function of the liver.

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    • "Our procedure from initial transcription factor screening to in vitro and in vivo characterization of iHepSCs is summarized in a diagram (Figure 1A). A total of 20 candidate factors, which were known to have critical roles either for embryonic liver organogenesis (Zaret and Grompe, 2008; Le Lay and Kaestner, 2010; Zaret, 2008) or for activation of oval cells in adult mouse livers (Jakubowski et al., 2005), were selected to test their potential capacity for inducing iHepSCs from MEFs (Table S1 available online). Similar with previous reports (Zaret, 2008; Okabe et al., 2009), expression of markers for hepatic stem cells, including EpCAM, alpha-fetoprotein (Afp), albumin (Alb), and transthyretin (Ttr), was used to determine the phenotype of iHepSCs. "
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    ABSTRACT: Recent studies have demonstrated direct reprogramming of fibroblasts into a range of somatic cell types, but to date stem or progenitor cells have only been reprogrammed for the blood and neuronal lineages. We previously reported generation of induced hepatocyte-like (iHep) cells by transduction of Gata4, Hnf1α, and Foxa3 in p19 Arf null mouse embryonic fibroblasts (MEFs). Here, we show that Hnf1β and Foxa3, liver organogenesis transcription factors, are sufficient to reprogram MEFs into induced hepatic stem cells (iHepSCs). iHepSCs can be stably expanded in vitro and possess the potential of bidirectional differentiation into both hepatocytic and cholangiocytic lineages. In the injured liver of fumarylacetoacetate hydrolase (Fah)-deficient mice, repopulating iHepSCs become hepatocyte-like cells. They also engraft as cholangiocytes into bile ducts of mice with DDC-induced bile ductular injury. Lineage conversion into bipotential expandable iHepSCs provides a strategy to enable efficient derivation of both hepatocytes and cholangiocytes for use in disease modeling and tissue engineering.
    Cell stem cell 07/2013; 13(3). DOI:10.1016/j.stem.2013.06.017 · 22.27 Impact Factor
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    • "The transcription factor Forkhead box protein sub-group O (FoxO) is a critical downstream effector of the insulin/insulin-like peptide signaling (IIS) and the nutrient sensor AMPK (Eijkelenboom and Burgering, 2013; Tzivion et al., 2011). FoxO has been implicated in a number of metabolic processes, including lipid metabolism (Zhang et al., 2006; Chakrabarti and Kandror, 2009; Le Lay and Kaestner, 2010). In murine adipocytes, Foxo1 induces ATGL expression thus causing lipolysis (Chakrabarti and Kandror, 2009; Chakrabarti et al., 2011). "
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    ABSTRACT: In a previous study, we have shown that the molting hormone, 20-hydroxyecdysone (20E), reduces insect food consumption resulting in fat body lipolysis during the non-feeding molting and pupation stages, and assumed that the transcription factor FoxO is involved in this process. To verify this hypothesis, we cloned foxO from the silkworm, Bombyx mori. During molting and pupation, FoxO is highly expressed and predominantly localizes in the nuclei of fat body cells. 20E induced foxO mRNA expression and FoxO nuclear localization resulting in an increase of FoxO transcriptional activity. RNAi of foxO prior to the 4(th) larval molting downregulated two lipase genes - the insect adipose triacylglycerol lipase homologue, brummer, and an acid lipase, acid lipase-1, in the fat body. Overexpression of the constitutively-active form of foxO (foxO(CA)) upregulated brummer and acid lipase-1 in both the fat body and Bombyx Bm-12 cells. Putative FoxO-response elements (FREs) are present in the promoter regions of brummer and acid lipase-1, and mutation of the FREs attenuated their FoxO-induced luciferase activities. ChIP assay revealed that FoxO binds directly to those FREs. Moreover, foxO(CA) overexpression in vivo doubled lipid concentration in the hemolymph, increased total lipase activity, and slightly but significantly reduced lipid content in the fat body. Taken together, we conclude that 20E increases the transcriptional activity of FoxO which, in turn, upregulates brummer and acid lipase-1 and induces lipolysis in the Bombyx fat body during molting and pupation.
    Insect biochemistry and molecular biology 06/2013; 43(9). DOI:10.1016/j.ibmb.2013.06.007 · 3.45 Impact Factor
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    • "Interestingly, we found that, in addition to the core TCF motif, the FoxA motif was one of the two enriched sequences within the TCF4 peaks (p value < 10 À20 ) (Figure 2A). The FoxA family transcription factors (FoxA1, FoxA2, FoxA3) are critical for mammalian liver development (Le Lay and Kaestner, 2010). In addition, FoxA1 has been shown to cooperate with estrogen receptor (ER) or androgen receptor (AR) to establish lineage-specific transcriptional programs in breast and prostate cancer cells (Hurtado et al., 2011; Robinson and Carroll, 2012). "
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    ABSTRACT: Dysregulation of Wnt signaling is closely associated with human liver tumorigenesis. However, liver cancer-specific Wnt transcriptional programs and downstream effectors remain poorly understood. Here, we identify tribbles homolog 2 (TRIB2) as a direct target of Wnt/TCF in liver cancer and demonstrate that transcription of Wnt target genes, including TRIB2, is coordinated by the TCF and FoxA transcription factors in liver cancer cells. We show that Wnt-TRIB2 activation is critical for cancer cell survival and transformation. Mechanistically, TRIB2 promotes protein stabilization of the YAP transcription coactivator through interaction with the βTrCP ubiquitin ligase. Furthermore, we find that TRIB2 relieves the liver tumor suppressor protein C/EBPα-mediated inhibition of YAP/TEAD transcriptional activation in liver cancer cells. Altogether, our study uncovers a regulatory mechanism underlying liver cancer-specific Wnt transcriptional output, and suggests that TRIB2 functions as a signaling nexus to integrate the Wnt/β-catenin, Hippo/YAP, and C/EBPα pathways in cancer cells.
    Molecular cell 06/2013; 51(2). DOI:10.1016/j.molcel.2013.05.013 · 14.02 Impact Factor
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