Trp53 and Rb1 regulate autophagy and ligand-dependent Hedgehog signaling

Cochrane, Catherine R. and Vaghjiani, Vijesh and Szczepny, Anette and Jayasekara, W. Samantha N. and Gonzalez-Rajal, Alvaro and Kikuchi, Kazu and McCaughan, Geoffrey W. and Burgess, Andrew and Gough, Daniel J. and Watkins, D. Neil and Cain, Jason E. (2020) Trp53 and Rb1 regulate autophagy and ligand-dependent Hedgehog signaling. Journal of Clinical Investigation. ISSN 0021-9738

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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.

Item Type: Article
Subjects: Q Science > Q Science (General)
R Medicine > R Medicine (General)
Divisions: Faculty of Medicine, Health and Life Sciences > School of Biological Sciences
Depositing User: Repository Administrator
Date Deposited: 25 Jun 2020 10:21
Last Modified: 11 Oct 2021 03:30

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