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The nuclear receptor DHR3 modulates dS6 kinase-dependent growth in Drosophila.

Montagne J, Lecerf C, Parvy JP, Bennion JM, Radimerski T, Ruhf ML, Zilbermann F, Vouilloz N, Stocker H, Hafen E, Kozma SC, Thomas G - PLoS Genet. (2010)

Bottom Line: S6 kinases (S6Ks) act to integrate nutrient and insulin signaling pathways and, as such, function as positive effectors in cell growth and organismal development.Consistent with these findings, we have identified an endogenous DHR3 isoform that lacks the DBD.These results provide the first molecular link between the dS6K pathway, critical in controlling nutrient-dependent growth, and that of DHR3, a major mediator of ecdysone signaling, which, acting together, coordinate metamorphosis.

View Article: PubMed Central - PubMed

Affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. montagne@cgm.cnrs-gif.fr

ABSTRACT
S6 kinases (S6Ks) act to integrate nutrient and insulin signaling pathways and, as such, function as positive effectors in cell growth and organismal development. However, they also have been shown to play a key role in limiting insulin signaling and in mediating the autophagic response. To identify novel regulators of S6K signaling, we have used a Drosophila-based, sensitized, gain-of-function genetic screen. Unexpectedly, one of the strongest enhancers to emerge from this screen was the nuclear receptor (NR), Drosophila hormone receptor 3 (DHR3), a critical constituent in the coordination of Drosophila metamorphosis. Here we demonstrate that DHR3, through dS6K, also acts to regulate cell-autonomous growth. Moreover, we show that the ligand-binding domain (LBD) of DHR3 is essential for mediating this response. Consistent with these findings, we have identified an endogenous DHR3 isoform that lacks the DBD. These results provide the first molecular link between the dS6K pathway, critical in controlling nutrient-dependent growth, and that of DHR3, a major mediator of ecdysone signaling, which, acting together, coordinate metamorphosis.

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DHR3–EP specifically counteracts Tsc-dependent growth suppression.Induction of UAS constructs and DHR3-EP by the eyeless promoter-directed Gal4 expression in the developing eye: (A) eye-Gal4 control; (B, D, E) DHR3-EP; (C, D) UAS-dTsc1 and UAS-dTsc2; (E, F) UAS-dPTEN.
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pgen-1000937-g002: DHR3–EP specifically counteracts Tsc-dependent growth suppression.Induction of UAS constructs and DHR3-EP by the eyeless promoter-directed Gal4 expression in the developing eye: (A) eye-Gal4 control; (B, D, E) DHR3-EP; (C, D) UAS-dTsc1 and UAS-dTsc2; (E, F) UAS-dPTEN.

Mentions: Recently, it has been suggested that the nutrient-effector arm of the TOR signaling pathway may have been integrated with that of the insulin-PI3K pathway following the rise of multicellular organisms [40]. Although it is clear that the nutrient and insulin pathways are also integrated in Drosophila, it is less clear where the point of integration resides [15], [17]. In part, this lack of clarity resides in the finding that depletion dTsc1/2, but not dPTEN, leads to dS6K activation, and that the overgrowth phenotype caused by loss of dTsc1/2, but not of dPTEN, is abolished by loss of dS6K [17]. Consistent with these findings, when either tumor suppressor is ectopically expressed in the developing eye, they suppress growth of this compartment, with co-expression of dS6K counteracting only the effects of dTsc1/2, but not of dPTEN (data not shown). This difference allows us to test whether DHR3-EP is acting exclusively on the dTsc1/2 growth response. As stated above, ectopic expression of either dTsc1/2 or dPTEN suppressed the growth of the developing eye (compare Figure 2A–2C). In contrast, ectopic expression of DHR3-EP had no apparent impact on eye development (compare Figure 2A and 2D), similar to what was observed in the wing (Figure 1D). However, ectopic expression of DHR3-EP, combined with either dTsc1/2 or dPTEN, largely counteracted the growth-suppressive effects due to dTsc1/2, but not of dPTEN (compare Figure 2E and 2B, and Figure 2F with 2C). These results support the notion that DHR3 acts to promote dS6K signaling.


The nuclear receptor DHR3 modulates dS6 kinase-dependent growth in Drosophila.

Montagne J, Lecerf C, Parvy JP, Bennion JM, Radimerski T, Ruhf ML, Zilbermann F, Vouilloz N, Stocker H, Hafen E, Kozma SC, Thomas G - PLoS Genet. (2010)

DHR3–EP specifically counteracts Tsc-dependent growth suppression.Induction of UAS constructs and DHR3-EP by the eyeless promoter-directed Gal4 expression in the developing eye: (A) eye-Gal4 control; (B, D, E) DHR3-EP; (C, D) UAS-dTsc1 and UAS-dTsc2; (E, F) UAS-dPTEN.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2865512&req=5

pgen-1000937-g002: DHR3–EP specifically counteracts Tsc-dependent growth suppression.Induction of UAS constructs and DHR3-EP by the eyeless promoter-directed Gal4 expression in the developing eye: (A) eye-Gal4 control; (B, D, E) DHR3-EP; (C, D) UAS-dTsc1 and UAS-dTsc2; (E, F) UAS-dPTEN.
Mentions: Recently, it has been suggested that the nutrient-effector arm of the TOR signaling pathway may have been integrated with that of the insulin-PI3K pathway following the rise of multicellular organisms [40]. Although it is clear that the nutrient and insulin pathways are also integrated in Drosophila, it is less clear where the point of integration resides [15], [17]. In part, this lack of clarity resides in the finding that depletion dTsc1/2, but not dPTEN, leads to dS6K activation, and that the overgrowth phenotype caused by loss of dTsc1/2, but not of dPTEN, is abolished by loss of dS6K [17]. Consistent with these findings, when either tumor suppressor is ectopically expressed in the developing eye, they suppress growth of this compartment, with co-expression of dS6K counteracting only the effects of dTsc1/2, but not of dPTEN (data not shown). This difference allows us to test whether DHR3-EP is acting exclusively on the dTsc1/2 growth response. As stated above, ectopic expression of either dTsc1/2 or dPTEN suppressed the growth of the developing eye (compare Figure 2A–2C). In contrast, ectopic expression of DHR3-EP had no apparent impact on eye development (compare Figure 2A and 2D), similar to what was observed in the wing (Figure 1D). However, ectopic expression of DHR3-EP, combined with either dTsc1/2 or dPTEN, largely counteracted the growth-suppressive effects due to dTsc1/2, but not of dPTEN (compare Figure 2E and 2B, and Figure 2F with 2C). These results support the notion that DHR3 acts to promote dS6K signaling.

Bottom Line: S6 kinases (S6Ks) act to integrate nutrient and insulin signaling pathways and, as such, function as positive effectors in cell growth and organismal development.Consistent with these findings, we have identified an endogenous DHR3 isoform that lacks the DBD.These results provide the first molecular link between the dS6K pathway, critical in controlling nutrient-dependent growth, and that of DHR3, a major mediator of ecdysone signaling, which, acting together, coordinate metamorphosis.

View Article: PubMed Central - PubMed

Affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. montagne@cgm.cnrs-gif.fr

ABSTRACT
S6 kinases (S6Ks) act to integrate nutrient and insulin signaling pathways and, as such, function as positive effectors in cell growth and organismal development. However, they also have been shown to play a key role in limiting insulin signaling and in mediating the autophagic response. To identify novel regulators of S6K signaling, we have used a Drosophila-based, sensitized, gain-of-function genetic screen. Unexpectedly, one of the strongest enhancers to emerge from this screen was the nuclear receptor (NR), Drosophila hormone receptor 3 (DHR3), a critical constituent in the coordination of Drosophila metamorphosis. Here we demonstrate that DHR3, through dS6K, also acts to regulate cell-autonomous growth. Moreover, we show that the ligand-binding domain (LBD) of DHR3 is essential for mediating this response. Consistent with these findings, we have identified an endogenous DHR3 isoform that lacks the DBD. These results provide the first molecular link between the dS6K pathway, critical in controlling nutrient-dependent growth, and that of DHR3, a major mediator of ecdysone signaling, which, acting together, coordinate metamorphosis.

Show MeSH