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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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ERK7 acts downstream of p53.(A) Overexpression of p53 in the IPCs (dILP2-Gal4) leads to increased erk7 mRNA levels as detected by in situ hybridization. (B, C) Knockdown of ERK7 suppresses dILP2 accumulation following p53 overexpression. Error bars represent standard deviation, (N≥10 brains). (D) Knockdown of ERK7 in the IPCs rescues the small pupal size caused by p53 overexpression. Error bars represent standard deviation (N = 3, 10 pupae/group). (E) ERK7 depletion in the IPCs partially rescues the developmental delay caused by p53 overexpression. Error bars represent standard deviation (N = 4, 30 larvae/group). **p<0.01, ***p<0.001 (Student's t-test).
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pgen-1004764-g006: ERK7 acts downstream of p53.(A) Overexpression of p53 in the IPCs (dILP2-Gal4) leads to increased erk7 mRNA levels as detected by in situ hybridization. (B, C) Knockdown of ERK7 suppresses dILP2 accumulation following p53 overexpression. Error bars represent standard deviation, (N≥10 brains). (D) Knockdown of ERK7 in the IPCs rescues the small pupal size caused by p53 overexpression. Error bars represent standard deviation (N = 3, 10 pupae/group). (E) ERK7 depletion in the IPCs partially rescues the developmental delay caused by p53 overexpression. Error bars represent standard deviation (N = 4, 30 larvae/group). **p<0.01, ***p<0.001 (Student's t-test).

Mentions: As we had observed that both p53 and ERK7 were essential for the inhibition of dILP2 secretion upon impaired ribosome biogenesis, we wanted to explore whether they belong to the same pathway. We hypothesized that ERK7 might be a downstream effector of p53. Supporting this idea, we observed that overexpression of wild type p53 in the IPCs led to elevated expression of erk7 mRNA as detected by in situ hybridization (Figure 6A). To further test the possible relevance of the p53-mediated regulation of erk7 in the IPCs, we performed genetic epistasis experiments. Indeed, depletion of ERK7 efficiently suppressed the dILP2 accumulation upon p53 overexpression (Figure 6B, C). Consistently, ERK7 RNAi also partially suppressed the reduction of pupal volume caused by p53 overexpression (Figure 6D) along with the delay in pupation (Figure 6E). Notably, the suppression by ERK7 RNAi was only partial, leaving open the possibility for a parallel, ERK7-independent, mechanism. In sum, our data implies that p53 and ERK7 belong to the same pathway and ERK7 acts as a downstream effector of p53 in inhibiting dILP2 secretion.


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

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

ERK7 acts downstream of p53.(A) Overexpression of p53 in the IPCs (dILP2-Gal4) leads to increased erk7 mRNA levels as detected by in situ hybridization. (B, C) Knockdown of ERK7 suppresses dILP2 accumulation following p53 overexpression. Error bars represent standard deviation, (N≥10 brains). (D) Knockdown of ERK7 in the IPCs rescues the small pupal size caused by p53 overexpression. Error bars represent standard deviation (N = 3, 10 pupae/group). (E) ERK7 depletion in the IPCs partially rescues the developmental delay caused by p53 overexpression. Error bars represent standard deviation (N = 4, 30 larvae/group). **p<0.01, ***p<0.001 (Student's t-test).
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pgen-1004764-g006: ERK7 acts downstream of p53.(A) Overexpression of p53 in the IPCs (dILP2-Gal4) leads to increased erk7 mRNA levels as detected by in situ hybridization. (B, C) Knockdown of ERK7 suppresses dILP2 accumulation following p53 overexpression. Error bars represent standard deviation, (N≥10 brains). (D) Knockdown of ERK7 in the IPCs rescues the small pupal size caused by p53 overexpression. Error bars represent standard deviation (N = 3, 10 pupae/group). (E) ERK7 depletion in the IPCs partially rescues the developmental delay caused by p53 overexpression. Error bars represent standard deviation (N = 4, 30 larvae/group). **p<0.01, ***p<0.001 (Student's t-test).
Mentions: As we had observed that both p53 and ERK7 were essential for the inhibition of dILP2 secretion upon impaired ribosome biogenesis, we wanted to explore whether they belong to the same pathway. We hypothesized that ERK7 might be a downstream effector of p53. Supporting this idea, we observed that overexpression of wild type p53 in the IPCs led to elevated expression of erk7 mRNA as detected by in situ hybridization (Figure 6A). To further test the possible relevance of the p53-mediated regulation of erk7 in the IPCs, we performed genetic epistasis experiments. Indeed, depletion of ERK7 efficiently suppressed the dILP2 accumulation upon p53 overexpression (Figure 6B, C). Consistently, ERK7 RNAi also partially suppressed the reduction of pupal volume caused by p53 overexpression (Figure 6D) along with the delay in pupation (Figure 6E). Notably, the suppression by ERK7 RNAi was only partial, leaving open the possibility for a parallel, ERK7-independent, mechanism. In sum, our data implies that p53 and ERK7 belong to the same pathway and ERK7 acts as a downstream effector of p53 in inhibiting dILP2 secretion.

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