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

Citation

Boglev, Y and Badrock, AP and Trotter, AJ and Du, Q and Richardson, EJ and Parslow, AC and Markmiller, AJ and Hall, NE and de Jong-Curtain, TA and Ng, AY and Verkade, H and Ober, EA and Field, HA and Shin, D and Shin, CH and Hannan, KM and Pearson, RB and Kim, S-H and Ess, KC and Lieschke, GJ and Stainier, DYR and Heath, JK, Autophagy induction is a Tor- and Tp53-independent cell survival response in a zebrafish model of disrupted ribosome biogenesis, PloS Genetics, 9, (2) Article e1003279. ISSN 1553-7390 (2013) [Refereed Article]


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Copyright 2013 Boglev et al. Licensed under [unspecified] Creative Commons Attribution

DOI: doi:10.1371/journal.pgen.1003279

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 (ttis450), 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 ttis450, 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 ttis450 larvae markedly reduces their lifespan. Somewhat surprisingly, autophagy induction in ttis450 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.

Item Details

Item Type:Refereed Article
Keywords:autophagy, ribosome biogenesis, zebrafish
Research Division:Biological Sciences
Research Group:Biochemistry and Cell Biology
Research Field:Cell Development, Proliferation and Death
Objective Division:Health
Objective Group:Clinical Health (Organs, Diseases and Abnormal Conditions)
Objective Field:Cancer and Related Disorders
Author:Trotter, AJ (Dr Andrew Trotter)
ID Code:116385
Year Published:2013
Web of Science® Times Cited:31
Deposited By:IMAS - Directorate
Deposited On:2017-05-09
Last Modified:2017-07-31
Downloads:6 View Download Statistics

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