Autophagy induction is a Tor- and Tp53-independent cell survival response in a zebrafish model of disrupted ribosome biogenesis.

Boglev, Y; Badrock, AP; Trotter, AJ; Du, Q; Richardson, EJ; Parslow, AC; Markmiller, SJ; Hall, NE; de Jong-Curtain, TA; Ng, AY; Verkade, H; Ober, EA; Field, HA; Shin, D; Shin, CH; Hannan, KM; Hannan, RD; Pearson, RB; Kim, SH; Ess, KC; Lieschke, GJ; Stainier, DY; Heath, JK

Author(s): Boglev, Y; Badrock, AP; Trotter, AJ; Du, Q; Richardson, EJ; Parslow, AC; Markmiller, SJ; Hall, NE; de Jong-Curtain, TA; Ng, AY; Verkade, H; Ober, EA; Field, HA; Shin, D; Shin, CH; Hannan, KM; Hannan, RD; Pearson, RB; Kim, SH; Ess, KC; Lieschke, GJ; Stainier, DY; Heath, JK;
Details: Publication Year 2013,Volume 9,Issue #2,Page e1003279
Journal Title: PLoS Genetics
Publication Type: Journal Article
Abstract: Ribosome biogenesis underpins cell growth and division. Disruptions in ribosome biogenesis and translation initiation are deleterious to development and underlie a spectrum of diseases known collectively as ribosomopathies. Here, we describe a novel zebrafish mutant, titania (tti(s450)), which harbours a recessive lethal mutation in pwp2h, a gene encoding a protein component of the small subunit processome. The biochemical impacts of this lesion are decreased production of mature 18S rRNA molecules, activation of Tp53, and impaired ribosome biogenesis. In tti(s450), the growth of the endodermal organs, eyes, brain, and craniofacial structures is severely arrested and autophagy is up-regulated, allowing intestinal epithelial cells to evade cell death. Inhibiting autophagy in tti(s450) larvae markedly reduces their lifespan. Somewhat surprisingly, autophagy induction in tti(s450) larvae is independent of the state of the Tor pathway and proceeds unabated in Tp53-mutant larvae. These data demonstrate that autophagy is a survival mechanism invoked in response to ribosomal stress. This response may be of relevance to therapeutic strategies aimed at killing cancer cells by targeting ribosome biogenesis. In certain contexts, these treatments may promote autophagy and contribute to cancer cells evading cell death.
Publisher: Public Library of Science
Keywords: Biosynthesis ; TOR signaling ; mutation ; Zebrafish ; Ribosomes ; Ribosomal DNA ; Larvae
Research Division(s): Chemical Biology
Publisher's Version: https://doi.org/10.1371/journal.pgen.1003279
Open Access at Publisher's Site: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567153/
Terms of Use/Rights Notice: Copyright: © 2013 Boglev et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Documents: journal.pgen.1003279.pdf - (8.08MB, application/pdf)

Creation Date: 2013-01-01 12:00:00