Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex

Cheng, Steven Y.; Bishop, J. Michael

doi:10.1073/pnas.082096999

Cited by 200 publications

(205 citation statements)

References 33 publications

(56 reference statements)

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“…Fourth, transcriptional activity of Gli molecules is also tightly regulated. Su(Fu) not only prevents nuclear translocation of Gli molecules, but also inhibits Gli1-mediated transcriptional activity (Cheng and Bishop, 2002). Table 1 summarizes major components of the Hh pathway in vertebrates.…”

Section: Signal Transduction Of the Hedgehog Pathwaymentioning

confidence: 99%

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

et al. 2009

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Section: Signal Transduction Of the Hedgehog Pathwaymentioning

confidence: 99%

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

et al. 2009

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“…It is not clear whether this activity requires the functional integrity of primary cilia. In addition, several studies also suggested a nuclear function of Sufu (Cheng and Bishop, 2002;Paces-Fessy et al, 2004), in which Sufu may function as a component of a transcription repressor complex. Regardless of the mode of action, attenuation of Sufu activity through degradation would be an effective way to alleviate the negative inhibition of Sufu on Shh signaling.…”

Section: Ubiquitination-mediated Degradation Of Sufu S Yue Et Almentioning

confidence: 99%

“…Human Sufu expression construct with a myc tag at the carboxyl terminus in pRK5 vector was described earlier (Cheng and Bishop, 2002). The Sufu-K257R mutant was created using the Quickchange site-directed mutagenesis kit (Stratagene, La Jolla, CA, USA).…”

Section: Plasmids and Cell Linesmentioning

confidence: 99%

“…The Gli-responsive 8 Â GliBS-Luc reporter was described earlier (Cheng and Bishop, 2002). In all, 0.4 Â 10 5 Sufu À/À MEFs (gifts from Dr Rune Toftgard, Svard et al, 2006) were transfected with 250 ng of 8 Â GliBS-Luc reporter, 25 ng pRL-TK (Promega, Madison, WI, USA) and 250 ng pRK5-hSufu-myc or mutant Sufu plasmids in each well of a 12-well plate.…”

Section: Luciferase Reporter Assaymentioning

confidence: 99%

“…Genetic and biochemical studies indicated that Drosophila Sufu binds, stabilizes and retains Ci (Cubitus interruptus) in the cytoplasm (Monnier et al, 1998;Ohlmeyer and Kalderon, 1998;Ingham and McMahon, 2001). These biochemical activities of Sufu are conserved in mammals (Kogerman et al, 1999;Jacob and Lum, 2007), and mammalian Sufu was also found to possess a nuclear activity in repressing Gli-mediated transcription via its interaction with SAP18 (Cheng and Bishop, 2002), a component of the Sin3-HDAC corepressor complex. Sufu mutations are present in 9% of medulloblastoma patients (Taylor et al, 2002), and mice that carry one target-inactivated Sufu allele exhibited heightened risk of developing medulloblastoma in p53 null background (Lee et al, 2007).…”

Section: Introductionmentioning

confidence: 97%

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Hedgehog signaling promotes the degradation of tumor suppressor Sufu through the ubiquitin–proteasome pathway

2008

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Sustained Sonic hedgehog (Shh) pathway activity is associated with tumorigenesis in a wide variety of tissues. Mutational inactivation of Shh receptor Patched (Ptch) and a downstream gene Suppressor of fused (Sufu), both of which are negative regulators of the pathway, increases susceptibility to cerebellum cancer in humans and mice. Sufu is a binding partner of Shh pathway transcription factor Gli. Recent data indicate that inactivation of Sufu, through either gene targeting in mice or RNAi-mediated silencing in cultured fibroblasts, is sufficient to turn on Shh target gene expression. Here, we report that Sufu is degraded rapidly in certain cancer cells and we show that Shh signaling promotes ubiquitination of Sufu, which leads to its destruction in the proteasomes. We identified an ubiquitin attachment site on K257 of Sufu, and showed that Sufu-K257R mutant is more potent as a transcription repressor and cell growth inhibitor because of increased stability. These results indicate that Shh signaling regulates Sufu activity by inducing its turnover via the ubiquitin-proteasome system.

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The hedgehog signaling network

Cohen

2003

American J of Med Genetics Pt A

387

230

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In the hedgehog signaling network, mutations result in various phenotypes, including, among others, holoprosencephaly, nevoid basal cell carcinoma syndrome, Pallister-Hall syndrome, Greig cephalopolysyndactyly, Rubinstein-Taybi syndrome, isolated basal cell carcinoma, and medulloblastoma. Active Hedgehog ligand is double lipid modified with a C-terminal cholesterol moiety and an N-terminal palmitate. Transport active Hedgehog from the signaling cell to the responding cell occurs through three mechanisms: 1). formation of multimeric Hedgehog which makes it soluble; 2). function of Dispatched in releasing the lipid-anchored protein from the signaling cell; and 3). movement across the plasma membrane of the responding cell by Tout-velu-dependent synthesis of heparan sulfate proteoglycan. In the responding cell, active Hedgehog binds to its receptor Patched, a 12-pass transmembrane protein, which frees Smoothened, an adjacent 7-pass transmembrane protein, for downstream signaling. Patched and Smoothened may shuttle oppositely between the plasma membrane and endocytic vesicles in response to active Hedgehog ligand. In downstream signaling, Cubitus interruptus (Gli proteins in vertebrates), Costal 2, Fused, and Suppressor of Fused form a tetrameric complex. Cubitus interruptus is a bifunctional transcription regulator. In the absence of active Hedgehog ligand, a truncated transcriptional repressor is generated that binds target genes and blocks their transcription. In the presence of active Hedgehog ligand, a full length transcriptional activator binds target genes and upregulates their transcription. Target genes include Wingless (Wnt gene family in vertebrates), Decapentaplegic (Bone Morphogenetic Proteins in vertebrates), and Patched. The upregulation of Patched expression, resulting in Patched protein at the cell membrane, sequesters Hedgehog and limits its spread beyond the cells in which it is produced. Thus, a balance is created by the antagonism of Hedgehog and Patched, whose relative concentrations alternate with respect to each other. Many more factors that are essential for the hedgehog signaling network are also discussed: Megalin, Rab23, Hip, GAS1, PKA, GSK3, CK1, Slimb, SAP18, and CBP.

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Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex

Cited by 200 publications

References 33 publications

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

Hedgehog signaling promotes the degradation of tumor suppressor Sufu through the ubiquitin–proteasome pathway

The hedgehog signaling network

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