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Genetic Elimination of Suppressor of Fused Reveals an Essential Repressor Function in the Mammalian Hedgehog Signaling Pathway

Department of Biosciences at Novum, Karolinska Institutet, SE-141 57 Huddinge, Sweden.
Developmental Cell (Impact Factor: 10.37). 03/2006; 10(2):187-97. DOI: 10.1016/j.devcel.2005.12.013
Source: PubMed

ABSTRACT The Hedgehog (Hh) pathway plays important roles during embryogenesis and carcinogenesis. Here, we show that ablation of the mouse Suppressor of fused (Sufu), an intracellular pathway component, leads to embryonic lethality at approximately E9.5 with cephalic and neural tube defects. Fibroblasts derived from Sufu(-/-) embryos showed high Gli-mediated Hh pathway activity that could not be modulated at the level of Smoothened and could only partially be blocked by PKA activation. Despite the robust constitutive pathway activation in the Sufu(-/-) fibroblasts, the GLI1 steady-state localization remained largely cytoplasmic, implying the presence of an effective nuclear export mechanism. Sufu(+/-) mice develop a skin phenotype with basaloid changes and jaw keratocysts, characteristic features of Gorlin syndrome, a human genetic disease linked to enhanced Hh signaling. Our data demonstrate that, in striking contrast to Drosophila, in mammals, Sufu has a central role, and its loss of function leads to potent ligand-independent activation of the Hh pathway.

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    • "In addition, it has been reported that mammalian Sufu directly modulates the transcriptional activity of Gli in the nucleus through recruitment of a corepressor complex (Cheng and Bishop, 2002; Paces-Fessy et al., 2004). The absence of Sufu results in constitutive Hh pathway activation similar to loss of Ptch1 in mouse but has no effect in Drosophila (Préat 1992; Cooper et al., 2005; Svärd et al., 2006). The differences in these phenotypes indicate that Sufu is the major inhibitor of Gli activity in mammals downstream of Ptch1, while multiple inhibitory mechanisms exist in flies (Jiang and Hui, 2008). "
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    ABSTRACT: The Hedgehog (Hh) signaling pathway plays crucial roles both in embryonic development and in adult stem cell function. The timing, duration and location of Hh signaling activity need to be tightly controlled. Abnormalities of Hh signal transduction lead to birth defects or malignant tumors. Recent data point to ubiquitination-related posttranslational modifications of several key Hh pathway components as an important mechanism of regulation of the Hh pathway. Here we review how ubiquitination regulates the localization, stability and activity of the key Hh signaling components.
    01/2015; DOI:10.1007/s11515-015-1343-5
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    • "Sufu is a major negative regulator of mammalian Hh signaling. Loss of Sufu in mammals leads to global Hh pathway activation and early embryonic lethality (Cooper et al. 2005; Svard et al. 2006). Sufu thus provides a key tool to understand how Hh signaling controls target gene activity. "
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    ABSTRACT: Control of Gli function by Suppressor of Fused (Sufu), a major negative regulator, is a key step in mammalian Hedgehog (Hh) signaling, but how this is achieved in the nucleus is unknown. We found that Hh signaling results in reduced Sufu protein levels and Sufu dissociation from Gli proteins in the nucleus, highlighting critical functions of Sufu in the nucleus. Through a proteomic approach, we identified several Sufu-interacting proteins, including p66β (a member of the NuRD [nucleosome remodeling and histone deacetylase] repressor complex) and Mycbp (a Myc-binding protein). p66β negatively and Mycbp positively regulate Hh signaling in cell-based assays and zebrafish. They function downstream from the membrane receptors, Patched and Smoothened, and the primary cilium. Sufu, p66β, Mycbp, and Gli are also detected on the promoters of Hh targets in a dynamic manner. Our results support a new model of Hh signaling in the nucleus. Sufu recruits p66β to block Gli-mediated Hh target gene expression. Meanwhile, Mycbp forms a complex with Gli and Sufu without Hh stimulation but remains inactive. Hh pathway activation leads to dissociation of Sufu/p66β from Gli, enabling Mycbp to promote Gli protein activity and Hh target gene expression. These studies provide novel insight into how Sufu controls Hh signaling in the nucleus. © 2014 Lin et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & Development 11/2014; 28(22):2547-63. DOI:10.1101/gad.249425.114 · 12.64 Impact Factor
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    • "Free GLI proteins are translocated to the nucleus where they can act as transcription factors. Targeted disruption of SUFU in mice results in a phenotype with Gorlin syndrome features [36], a skin cancer condition associated with constitutive HH activation due to LOF mutation of PTCH-1 [37]. Thus, SUFU appears to be a tumor suppressor and a major negative regulator of HH signaling as it controls the production of GLI activators and repressors essential for graded HH signaling, such is observed in the developing embryo. "
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