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Sheng, Tao; Li, Chang-Jiu; Zhang, Xiaoli; Chi, Sumin; He, Nonggao; Chen, Kai; McCormick, Frank; Gatalica, Zoran; Xie, Jingwu

doi:10.1186/1476-4598-3-29

Cited by 394 publications

(149 citation statements)

References 63 publications

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“…Germline Sufu mutations have been identified in medulloblastoma (Taylor et al , 2002; Kool et al , 2014) and associated with the development of medulloblastoma in Gorlin syndrome (Pastorino et al , 2009; Kijima et al , 2012; Smith et al , 2014). Furthermore, somatic Sufu mutations have been identified in multiple other malignancies, including prostate cancer (Sheng et al , 2004). Sufu has a pivotal role in Hh signaling and is a relevant tumor suppressor, but the players involved in controlling Sufu levels are unknown and the relevance for cancer proliferation remains unrecognized.…”

Section: Introductionmentioning

confidence: 99%

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

et al. 2016

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Skp1‐Cul1‐F‐box protein (SCF) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumor suppressor by maintaining the Gli (Glioma‐associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumor growth are unknown. Here, we show that Fbxl17 (F‐box and leucine‐rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, which increases Sufu turnover through Fbxl17‐mediated polyubiquitylation and leads to a sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight the perturbation of the Fbxl17–Sufu axis in the pathogenesis of medulloblastoma.

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Section: Introductionmentioning

confidence: 99%

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

et al. 2016

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“…In several cases, Smo-independent activation mechanisms have been documented, such as mutations in or loss of heterozygosity of the SUFU gene, which was found in medulloblastoma (20,21), prostate cancer (22), rhabdomyosarcoma (7), and a human lung cancer cell line (23). In addition, other downstream pathway activation mechanisms have been revealed, such as REN deletions (15), GLI gene amplifications (24)(25)(26), GLI1 chromosomal translocations (27), or GLI2 protein stabilization (28).…”

mentioning

confidence: 99%

Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists

Lauth

Bergström²,

Shimokawa³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

735

693

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The developmentally important Hedgehog (Hh) signaling pathway has recently been implicated in several forms of solid cancer. Current drug development programs focus on targeting the protooncogene Smoothened, a key transmembrane pathway member. These drug candidates, albeit promising, do not address the scenario in which pathway activation occurs downstream of Smoothened, as observed in cases of medulloblastoma, glioma, pericytoma, breast cancer, and prostate cancer. A cellular screen for small-molecule antagonists of GLI-mediated transcription, which constitutes the final step in the Hh pathway, revealed two molecules that are able to selectively inhibit GLI-mediated gene transactivation. We provide genetic evidence of downstream pathway blockade by these compounds and demonstrate the ineffectiveness of upstream antagonists such as cyclopamine in such situations. Mechanistically, both inhibitors act in the nucleus to block GLI function, and one of them interferes with GLI1 DNA binding in living cells. Importantly, the discovered compounds efficiently inhibited in vitro tumor cell proliferation in a GLI-dependent manner and successfully blocked cell growth in an in vivo xenograft model using human prostate cancer cells harboring downstream activation of the Hh pathway.

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“…Recent studies have stressed the importance of Hh signaling in human prostate cancer (13)(14)(15)20). Elevated Hh signaling pathway activity may distinguish metastatic from localized prostate cancer, and pathway manipulation can modulate invasiveness and metastasis (13).…”

mentioning

confidence: 99%

Gli2 Is Targeted for Ubiquitination and Degradation by β-TrCP Ubiquitin Ligase

Bhatia

Thiyagarajan

Elcheva

et al. 2006

Journal of Biological Chemistry

123

120

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The Hedgehog (Hh) signaling pathway plays a crucial role in embryogenesis and has been linked to the development of several human malignancies. The transcription factor Gli2 plays a key role in the transduction of Hh signals by modulating transcription of some Hh target genes, yet the mechanisms that control Gli2 protein expression are largely unknown. Here we report that ␤-transducin repeat-containing protein (␤-TrCP) E3 ubiquitin ligase is required for Gli2 degradation. ␤-TrCP2 directly binds wild type Gli2 and promotes its ubiquitination. Single amino acid substitution in Gli2 putative binding site inhibits its interaction with ␤-TrCP2, its ubiquitination, and stabilizes the Gli2 protein. Stable Gli2 mutant is expressed in higher levels and is more potent in the activation of Gli-dependent transcription as compared with wild type Gli2. We also found that GLI2 protein is expressed highly in prostate cancer cell lines and primary tumors, whereas the level of GLI2 mRNA is not appreciably different in normal and neoplastic prostate. These data identify ␤-TrCP2 as a pivotal regulator of Gli2 expression and point to an important role for posttranslational modulation of GLI2 protein levels in Hh pathway-associated human prostate cancer.

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Cited by 394 publications

References 63 publications

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists

Gli2 Is Targeted for Ubiquitination and Degradation by β-TrCP Ubiquitin Ligase

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