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
AU - Du, Qian
AU - Richardson, Elsbeth J
AU - Parslow, Adam
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
AU - Hannan, Katherine M
AU - Hannan, Ross Duncan
AU - Pearson, Richard Bruce
AU - Kim, Seok-Hyung
AU - Ess, Kevin C
AU - Lieschke, Graham
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.
UR - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567153/pdf/pgen.1003279.pdf
U2 - 10.1371/journal.pgen.1003279
DO - 10.1371/journal.pgen.1003279
M3 - Article
SN - 1553-7390
VL - 9
SP - 1
EP - 18
JO - PLoS Genetics
JF - PLoS Genetics
IS - 2 (Art # e1003279)
ER -