Trp53 and Rb1 regulate autophagy and ligand-dependent Hedgehog signaling

Trp53 and Rb1 regulate autophagy and ligand-dependent Hedgehog signaling.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1172/JCI132513
Journal or Publication Title: Journal of Clinical Investigation
Date: 2020
Divisions: Liver Injury and Cancer
Depositing User: General Admin
Identification Number: 10.1172/JCI132513
ISSN: 0021-9738
Date Deposited: 04 Jan 2021 00:54
Abstract:

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.

Creators:
Creators
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Cochrane, Catherine R.
UNSPECIFIED
Vaghjiani, Vijesh
UNSPECIFIED
Szczepny, Anette
UNSPECIFIED
Jayasekara, W. Samantha N.
UNSPECIFIED
Gonzalez-Rajal, Alvaro
UNSPECIFIED
Kikuchi, Kazu
UNSPECIFIED
McCaughan, Geoffrey W.
UNSPECIFIED
Burgess, Andrew
UNSPECIFIED
Gough, Daniel J.
UNSPECIFIED
Watkins, D. Neil
UNSPECIFIED
Cain, Jason E.
UNSPECIFIED
Last Modified: 04 Jan 2021 00:54
URI: https://eprints.centenary.org.au/id/eprint/797

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