Trp53 and Rb1 regulate autophagy and ligand-dependent Hedgehog signaling
| العنوان: | Trp53 and Rb1 regulate autophagy and ligand-dependent Hedgehog signaling |
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| المؤلفون: | Anette Szczepny, Alvaro Gonzalez-Rajal, Andrew Burgess, W. Samantha N. Jayasekara, Kazu Kikuchi, Vijesh Vaghjiani, Catherine R Cochrane, Geoffrey W. McCaughan, Daniel J. Gough, D. Neil Watkins, Jason E. Cain |
| المصدر: | J Clin Invest |
| بيانات النشر: | American Society for Clinical Investigation, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Lung Neoplasms, Transcription, Genetic, Mice, Transgenic, Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Transcription (biology), Autophagy, Animals, Humans, Hedgehog Proteins, KIF3A, Hedgehog, Cilium, Neoplasms, Experimental, General Medicine, Small Cell Lung Carcinoma, Transmembrane protein, Hedgehog signaling pathway, Cell biology, Retinoblastoma Binding Proteins, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Tumor Suppressor Protein p53, Smoothened, Signal Transduction, Research Article |
| الوصف: | Ligand-dependent activation of Hedgehog (Hh) signaling in cancer occurs without mutations in canonical pathway genes. Consequently, the genetic basis of Hh pathway activation in adult solid tumors, such as small-cell lung cancer (SCLC), is unknown. Here we show that combined inactivation of Trp53 and Rb1, a defining genetic feature of SCLC, leads to hypersensitivity to Hh ligand in vitro, and during neural tube development in vivo. This response is associated with the aberrant formation of primary cilia, an organelle essential for canonical Hh signaling through smoothened, a transmembrane protein targeted by small-molecule Hh inhibitors. We further show that loss of both Trp53 and Rb1 disables transcription of genes in the autophagic machinery necessary for the degradation of primary cilia. In turn, we also demonstrate a requirement for Kif3a, a gene essential for the formation of primary cilia, in a mouse model of SCLC induced by conditional deletion of both Trp53 and Rb1 in the adult airway. Our results provide a mechanistic framework for therapeutic targeting of ligand-dependent Hh signaling in human cancers with somatic mutations in both TP53 and RB1. |
| تدمد: | 1558-8238 0021-9738 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f357039e03dfd786bcd7a84a0f77a487Test https://doi.org/10.1172/jci132513Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f357039e03dfd786bcd7a84a0f77a487 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15588238 00219738 |
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