Trp53 and Rb1 regulate autophagy and ligand-dependent Hedgehog signaling
| Autor: | 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 |
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| Rok vydání: | 2020 |
| Předmět: |
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 |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci132513 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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