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Mechanistic target of rapamycin (MTOR) cooperates with Hedgehog (HH) signaling, but the underlying mechanisms are incompletely understood. Here we provide genetic, biochemical, and pharmacologic evidence that MTOR complex 1 (mTORC1)-dependent translation is a prerequisite for HH signaling. The genetic loss of mTORC1 function inhibited HH signaling-driven growth of the cerebellum and medulloblastoma. Inhibiting translation or mTORC1 blocked HH signaling. Depleting 4EBP1, an mTORC1 target that inhibits translation, alleviated the dependence of HH signaling on mTORC1. Consistent with this, phosphorylated 4EBP1 levels were elevated in HH signaling-driven medulloblastomas in mice and humans. In mice, an mTORC1 inhibitor suppressed medulloblastoma driven by a mutant SMO that is inherently resistant to existing SMO inhibitors, prolonging the survival of the mice. Our study reveals that mTORC1-mediated translation is a key component of HH signaling and an important target for treating medulloblastoma and other cancers driven by HH signaling.
Pubmed ID: 29103956 RIS Download
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This monoclonal targets YAP (63.7)
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View all literature mentionsThis monoclonal targets 4E-BP1 (53H11) Rabbit mAb
View all literature mentionsThis monoclonal targets 4E-BP1, phospho (Thr37 / Thr46)
View all literature mentionsMus musculus with name B6N.129-Ptch1tm1Hahn/J from IMSR.
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Mus musculus with name STOCK Ptprcb Thy1
Mus musculus with name B6.Cg-Rptortm1.1Dmsa/J from IMSR.
View all literature mentionsMus musculus with name FVB-Tg(GFAP-cre)25Mes/J from IMSR.
View all literature mentionsMus musculus with name STOCK Gt(ROSA)26Sortm1(Smo/EYFP)Amc/J from IMSR.
View all literature mentionsCell line NIH 3T3 is a Spontaneously immortalized cell line with a species of origin Mus musculus
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