Autophagy induction is a Tor- and Tp53-independent cell survival response in a zebrafish model of disrupted ribosome biogenesis
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Autophagy induction is a Tor- and Tp53-independent cell survival response in a zebrafish model of disrupted ribosome biogenesis. / Boglev, Yeliz; Badrock, Andrew P; Trotter, Andrew J; Du, Qian; Richardson, Elsbeth J; Parslow, Adam C; Markmiller, Sebastian J; Hall, Nathan E; de Jong-Curtain, Tanya A; Ng, Annie Y; Verkade, Heather; Ober, Elke A; Field, Holly A; Shin, Donghun; Shin, Chong H; Hannan, Katherine M; Hannan, Ross D; Pearson, Richard B; Kim, Seok-Hyung; Ess, Kevin C; Lieschke, Graham J; Stainier, Didier Y R; Heath, Joan K.
In: P L o S Genetics (Online), Vol. 9, No. 2, 2013, p. e1003279.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Autophagy induction is a Tor- and Tp53-independent cell survival response in a zebrafish model of disrupted ribosome biogenesis
AU - Boglev, Yeliz
AU - Badrock, Andrew P
AU - Trotter, Andrew J
AU - Du, Qian
AU - Richardson, Elsbeth J
AU - Parslow, Adam C
AU - Markmiller, Sebastian J
AU - Hall, Nathan E
AU - de Jong-Curtain, Tanya A
AU - Ng, Annie Y
AU - Verkade, Heather
AU - Ober, Elke A
AU - Field, Holly A
AU - Shin, Donghun
AU - Shin, Chong H
AU - Hannan, Katherine M
AU - Hannan, Ross D
AU - Pearson, Richard B
AU - Kim, Seok-Hyung
AU - Ess, Kevin C
AU - Lieschke, Graham J
AU - Stainier, Didier Y R
AU - Heath, Joan K
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - Animals
KW - Autophagy
KW - Cell Cycle Proteins
KW - Cell Survival
KW - Genes, Lethal
KW - Mutation
KW - Protein Biosynthesis
KW - RNA, Ribosomal, 18S
KW - Ribosomes
KW - TOR Serine-Threonine Kinases
KW - Tumor Suppressor Protein p53
KW - Zebrafish
KW - Zebrafish Proteins
U2 - 10.1371/journal.pgen.1003279
DO - 10.1371/journal.pgen.1003279
M3 - Journal article
C2 - 23408911
VL - 9
SP - e1003279
JO - P L o S Genetics
JF - P L o S Genetics
SN - 1553-7390
IS - 2
ER -
ID: 130759303