期刊
EMBO JOURNAL
卷 35, 期 13, 页码 1400-1416出版社
WILEY-BLACKWELL
DOI: 10.15252/embj.201593374
关键词
F-box protein; Fbxl17; Hedgehog signaling; medulloblastoma; Sufu
资金
- Medical Research Council (MRC) [MC_PC_12007]
- Cancer Research UK [C5255/A12678]
- Swedish Research Council
- Swedish Cancer Society
- Center for Innovative Medicine at Karolinska Institutet
- Wellcome Trust [097813/Z/11/Z]
- AIRC Grant IG [14723]
- [133/075]
- Cancer Research UK [16945, 23969, 16466] Funding Source: researchfish
- Medical Research Council [G0501068, MR/L001209/1, MC_PC_12007] Funding Source: researchfish
- MRC [G0501068, MC_PC_12007] Funding Source: UKRI
- Wellcome Trust [097813/Z/11/Z] Funding Source: Wellcome Trust
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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