Drosophila insulin and target of rapamycin (TOR) pathways regulate GSK3 beta activity to control Myc stability and determine Myc expression in vivo

Parisi, Federica; Riccardo, Sara; Daniel, Margaret A.; Saqcena, Mahesh; Kundu, Nandini; Pession, Annalisa; Grifoni, Daniela; Stocker, Hugo; Tabak, Esteban G.; Bellosta, Paola

doi:10.1186/1741-7007-9-65

Cited by 61 publications

(59 citation statements)

References 58 publications

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“…If Myc’s regulation of cellular growth rate is key to its ability to modulate lifespan, it is tempting to suggest that this may be via the Insulin (IIS) signaling pathway that has been previously implicated in aging across a number of species [53]. Myc can regulate the IIS downstream target gene eIF4E in mammalian cells [54], [55], and has been linked to both Foxo and TOR in flies, although this appears to be highly tissue-specific [56], [57]. Myc may therefore be a new component to this highly conserved lifespan/aging pathway.…”

Section: Discussionmentioning

confidence: 99%

Myc-Dependent Genome Instability and Lifespan in Drosophila

et al. 2013

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The Myc family of transcription factors are key regulators of cell growth and proliferation that are dysregulated in a large number of human cancers. When overexpressed, Myc family proteins also cause genomic instability, a hallmark of both transformed and aging cells. Using an in vivo lacZ mutation reporter, we show that overexpression of Myc in Drosophila increases the frequency of large genome rearrangements associated with erroneous repair of DNA double-strand breaks (DSBs). In addition, we find that overexpression of Myc shortens adult lifespan and, conversely, that Myc haploinsufficiency reduces mutation load and extends lifespan. Our data provide the first evidence that Myc may act as a pro-aging factor, possibly through its ability to greatly increase genome instability.

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Section: Discussionmentioning

confidence: 99%

Myc-Dependent Genome Instability and Lifespan in Drosophila

et al. 2013

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“…dMyc is another important mediator of nutritional gene expression, particularly the transcription of genes involved in ribosome biogenesis (Grewal et al, 2005;Li et al, 2010;Teleman et al, 2008). Both the insulin/PI3K and TOR branches of the nutrient-sensing pathway can regulate Myc, at the mRNA and protein levels respectively (Parisi et al, 2011;Teleman et al, 2008). Further transcription factors known to regulate gene expression downstream of TOR include SREBP, involved in lipid and sterol biosynthesis, and Sugarbabe, which mediates the effect of nutrient deprivation on dILP release (Porstmann et al, 2008;Varghese et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

DREF is required for cell and organismal growth in Drosophila and functions downstream of the nutrition/TOR pathway

Killip

Grewal

2012

Developmental Biology

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Nutrient availability is a key determinant of animal growth. The conserved insulin/PI3 kinase and TOR kinase signaling pathways are two of the best characterized regulators of cell and tissue growth in response to nutritional conditions. Studies in Drosophila larvae show that one mechanism by which these pathways drive growth is by regulating the expression of metabolic genes, especially those genes required for protein synthesis. Here we examine a role for the transcription factor DREF in mediating some of these transcriptional and growth responses. We find that loss of DREF leads to a decrease in organismal growth. These effects are in part due to a requirement for DREF function in cell-autonomous growth. We also uncover a non-autonomous role for DREF activity in the larval fat body. Previous studies show that activation of TOR in the fat body couples nutrition to insulin release from the brain; we find that inhibition of DREF in the fat body can phenocopy effects of nutrient deprivation and fat-specific TOR inhibition, leading to a reduction in systemic insulin signaling, delayed larval growth and smaller final size. Using genetic epistasis, we find that DREF is required for growth downstream of TOR, but not insulin/PI3K signaling. Moreover, we show that TOR can control DREF mRNA levels, in part via the transcription factor dMyc. Finally we show that DREF is required for normal expression of many ribosome biogenesis genes, suggesting that one mechanism by which DREF is required for growth is through the control of protein synthetic capacity. Together these findings suggest DREF is an essential transcription factor in the nutritional control of cell and tissue growth during Drosophila development. Given that DREF is conserved, this role may also be important in the control of growth in other animals.

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“…Unlike c-Myc, which was shown to have a single Myc BoxI phosphodegron associated with Fbw7 binding, several domains containing putative Ago-interacting motifs were shown in dMyc to mediate Casein kinase 1 (CK1)α-, CK1ε-and GSK3β-dependent protein degradation. Although their link to Ago function has not been precisely established, it is clear that GSK3β plays a key role in Ago-mediated dMyc ubiquitylation and degradation (Galletti et al, 2009;Moberg et al, 2004;Parisi et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

TheDrosophilaubiquitin-specific protease Puffyeye regulates dMyc-mediated growth

Anderson

Secombe

et al. 2013

Development

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The essential and highly conserved role of Myc in organismal growth and development is dependent on the control of Myc protein abundance. It is now well established that Myc levels are in part regulated by ubiquitin-dependent proteasomal degradation. Using a genetic screen for modifiers of Drosophila Myc (dMyc)-induced growth, we identified and characterized a ubiquitin-specific protease (USP), Puffyeye (Puf), as a novel regulator of dMyc levels and function in vivo. We show that puf genetically and physically interacts with dMyc and the ubiquitin ligase archipelago (ago) to modulate a dMyc-dependent cell growth phenotype, and that varying Puf levels in both the eye and wing phenocopies the effects of altered dMyc abundance. Puf containing point mutations within its USP enzymatic domain failed to alter dMyc levels and displayed no detectable phenotype, indicating the importance of deubiquitylating activity for Puf function. We find that dMyc induces Ago, indicating that dMyc triggers a negative-feedback pathway that is modulated by Puf. In addition to its effects on dMyc, Puf regulates both Ago and its cell cycle substrate Cyclin E. Therefore, Puf influences cell growth by controlling the stability of key regulatory proteins.

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Drosophila insulin and target of rapamycin (TOR) pathways regulate GSK3 beta activity to control Myc stability and determine Myc expression in vivo

Cited by 61 publications

References 58 publications

Myc-Dependent Genome Instability and Lifespan in Drosophila

Myc-Dependent Genome Instability and Lifespan in Drosophila

DREF is required for cell and organismal growth in Drosophila and functions downstream of the nutrition/TOR pathway

TheDrosophilaubiquitin-specific protease Puffyeye regulates dMyc-mediated growth

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