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p53- and ERK7-dependent ribosome surveillance response regulates Drosophila insulin-like peptide secretion.

Hasygar K, Hietakangas V - PLoS Genet. (2014)

Bottom Line: A downstream effector of this growth inhibitory response is an atypical MAP kinase ERK7 (ERK8/MAPK15), which is upregulated in the IPCs following impaired ribosome biogenesis as well as starvation.Moreover, we provide evidence that p53 and ERK7 contribute to the inhibition of dILP secretion upon starvation.Thus, we conclude that a cell autonomous ribosome surveillance response, which leads to upregulation of ERK7, inhibits dILP secretion to impede tissue growth under limiting dietary conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Biosciences & Institute of Biotechnology, University of Helsinki, Helsinki, Finland.

ABSTRACT
Insulin-like signalling is a conserved mechanism that coordinates animal growth and metabolism with nutrient status. In Drosophila, insulin-producing median neurosecretory cells (IPCs) regulate larval growth by secreting insulin-like peptides (dILPs) in a diet-dependent manner. Previous studies have shown that nutrition affects dILP secretion through humoral signals derived from the fat body. Here we uncover a novel mechanism that operates cell autonomously in the IPCs to regulate dILP secretion. We observed that impairment of ribosome biogenesis specifically in the IPCs strongly inhibits dILP secretion, which consequently leads to reduced body size and a delay in larval development. This response is dependent on p53, a known surveillance factor for ribosome biogenesis. A downstream effector of this growth inhibitory response is an atypical MAP kinase ERK7 (ERK8/MAPK15), which is upregulated in the IPCs following impaired ribosome biogenesis as well as starvation. We show that ERK7 is sufficient and essential to inhibit dILP secretion upon impaired ribosome biogenesis, and it acts epistatically to p53. Moreover, we provide evidence that p53 and ERK7 contribute to the inhibition of dILP secretion upon starvation. Thus, we conclude that a cell autonomous ribosome surveillance response, which leads to upregulation of ERK7, inhibits dILP secretion to impede tissue growth under limiting dietary conditions.

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p53 and ERK7 regulate dILP2 secretion upon starvation.Knockdown of p53 (A, B) or ERK7 (C, D) in the IPCs partially suppresses dILP2 accumulation upon starvation. Error bars represent standard deviation, (N≥10 brains). Third instar non-wandering larvae were starved for 15 h on PBS, 1% sucrose, 0.4% agar. IPCs are labelled by GFP (green) and dILP2 is shown as red. *p<0.05, **p<0.01, ***p<0.001 (Student's t-test).
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pgen-1004764-g007: p53 and ERK7 regulate dILP2 secretion upon starvation.Knockdown of p53 (A, B) or ERK7 (C, D) in the IPCs partially suppresses dILP2 accumulation upon starvation. Error bars represent standard deviation, (N≥10 brains). Third instar non-wandering larvae were starved for 15 h on PBS, 1% sucrose, 0.4% agar. IPCs are labelled by GFP (green) and dILP2 is shown as red. *p<0.05, **p<0.01, ***p<0.001 (Student's t-test).

Mentions: As ribosome biogenesis is dependent on nutrients [1], [12], [35], and erk7 expression was elevated upon starvation (Figure 4A, D), we postulated that perhaps the p53- and ERK7-dependent ribosome surveillance response contributes to dILP accumulation in the IPCs upon starvation. This proved to be the case, as inhibition of either p53 (Figure 7A, B; Figure S10) or ERK7 (Figure 7C, D) in the IPCs partially reduced the accumulation of dILP2 following starvation of the larvae. While we cannot rule out the possibility that the knockdown of p53 and ERK7 affects dILP2 translation in this setting, the most parsimonious explanation is that p53 and ERK7 contribute to dILP2 secretion upon starvation.


p53- and ERK7-dependent ribosome surveillance response regulates Drosophila insulin-like peptide secretion.

Hasygar K, Hietakangas V - PLoS Genet. (2014)

p53 and ERK7 regulate dILP2 secretion upon starvation.Knockdown of p53 (A, B) or ERK7 (C, D) in the IPCs partially suppresses dILP2 accumulation upon starvation. Error bars represent standard deviation, (N≥10 brains). Third instar non-wandering larvae were starved for 15 h on PBS, 1% sucrose, 0.4% agar. IPCs are labelled by GFP (green) and dILP2 is shown as red. *p<0.05, **p<0.01, ***p<0.001 (Student's t-test).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230838&req=5

pgen-1004764-g007: p53 and ERK7 regulate dILP2 secretion upon starvation.Knockdown of p53 (A, B) or ERK7 (C, D) in the IPCs partially suppresses dILP2 accumulation upon starvation. Error bars represent standard deviation, (N≥10 brains). Third instar non-wandering larvae were starved for 15 h on PBS, 1% sucrose, 0.4% agar. IPCs are labelled by GFP (green) and dILP2 is shown as red. *p<0.05, **p<0.01, ***p<0.001 (Student's t-test).
Mentions: As ribosome biogenesis is dependent on nutrients [1], [12], [35], and erk7 expression was elevated upon starvation (Figure 4A, D), we postulated that perhaps the p53- and ERK7-dependent ribosome surveillance response contributes to dILP accumulation in the IPCs upon starvation. This proved to be the case, as inhibition of either p53 (Figure 7A, B; Figure S10) or ERK7 (Figure 7C, D) in the IPCs partially reduced the accumulation of dILP2 following starvation of the larvae. While we cannot rule out the possibility that the knockdown of p53 and ERK7 affects dILP2 translation in this setting, the most parsimonious explanation is that p53 and ERK7 contribute to dILP2 secretion upon starvation.

Bottom Line: A downstream effector of this growth inhibitory response is an atypical MAP kinase ERK7 (ERK8/MAPK15), which is upregulated in the IPCs following impaired ribosome biogenesis as well as starvation.Moreover, we provide evidence that p53 and ERK7 contribute to the inhibition of dILP secretion upon starvation.Thus, we conclude that a cell autonomous ribosome surveillance response, which leads to upregulation of ERK7, inhibits dILP secretion to impede tissue growth under limiting dietary conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Biosciences & Institute of Biotechnology, University of Helsinki, Helsinki, Finland.

ABSTRACT
Insulin-like signalling is a conserved mechanism that coordinates animal growth and metabolism with nutrient status. In Drosophila, insulin-producing median neurosecretory cells (IPCs) regulate larval growth by secreting insulin-like peptides (dILPs) in a diet-dependent manner. Previous studies have shown that nutrition affects dILP secretion through humoral signals derived from the fat body. Here we uncover a novel mechanism that operates cell autonomously in the IPCs to regulate dILP secretion. We observed that impairment of ribosome biogenesis specifically in the IPCs strongly inhibits dILP secretion, which consequently leads to reduced body size and a delay in larval development. This response is dependent on p53, a known surveillance factor for ribosome biogenesis. A downstream effector of this growth inhibitory response is an atypical MAP kinase ERK7 (ERK8/MAPK15), which is upregulated in the IPCs following impaired ribosome biogenesis as well as starvation. We show that ERK7 is sufficient and essential to inhibit dILP secretion upon impaired ribosome biogenesis, and it acts epistatically to p53. Moreover, we provide evidence that p53 and ERK7 contribute to the inhibition of dILP secretion upon starvation. Thus, we conclude that a cell autonomous ribosome surveillance response, which leads to upregulation of ERK7, inhibits dILP secretion to impede tissue growth under limiting dietary conditions.

Show MeSH
Related in: MedlinePlus