Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway.

By O. Puig, M. Marr, M. Ruhf, R. Tjian. Genes & Development, 2003

632 citations recorded by the source corpus.

The Drosophila insulin receptor (dInR) regulates cell growth and proliferation through the dPI3K/dAkt pathway, which is conserved in metazoan organisms. Here we report the identification and functional characterization of the Drosophila forkhead-related transcription factor dFOXO, a key component of the insulin signaling cascade. dFOXO is phosphorylated by dAkt upon insulin treatment, leading to cytoplasmic retention and inhibition of its transcriptional activity. Mutant dFOXO lacking dAkt phosphorylation sites no longer responds to insulin inhibition, remains in the nucleus, and is constitutively active. dFOXO activation in S2 cells induces growth arrest and activates two key players of the dInR/dPI3K/dAkt pathway: the translational regulator d4EBP and the dInR itself. Induction of d4EBP likely leads to growth inhibition by dFOXO, whereas activation of dInR provides a novel transcriptionally induced feedback control mechanism. Targeted expression of dFOXO in fly tissues regulates organ size by specifying cell number with no effect on cell size. Our results establish dFOXO as a key transcriptional regulator of the insulin pathway that modulates growth and proliferation.

Subfields: Aging, Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/dfdb5f31ef2adcfdfe4fca7ce622f0013c9edd52

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Aging

1. Rute Martins
2. W. Link
3. G. Lithgow
4. R. DePinho

In Molecular Biology

1. Mike Tyers
2. Paul Jorgensen
3. Di Chen
4. G. Juhász
5. R. C. Scott
6. D. Riddle
7. Kailiang Jia
8. T. P. Neufeld

Citations in the corpus

• The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span (2004, background): “Recently, FOXO, the DrosophilaDAF-16 ortholog, was reported to positively regulate the transcription of 4E-BP (Puig et al., 2003).”
• Long live FOXO: unraveling the role of FOXO proteins in aging and longevity (2015, background): “Mutant dFoxO lacking dAKT phosphorylation sites does not respond to insulin inhibition and is constitutively active in the nucleus (Puig et al., 2003). dFoxO activation induces growth arrest and increases the expression of two key players of the dInR/dPI3K/dAKT pathway: the translational regulator…”
• FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis (2009, background): “Together, these observations suggest that FoxOs function to constrain the cycling of NSCs and/or progenitor cells, but not their size, an observation in line with Drosophila FoxO control of cell proliferation but not cell size (Puig et al., 2003).”
• How cells coordinate growth and division. (2004, background): “The IGF/PI3K signaling pathway as well as the closely intertwined Tsc1, Tsc2, S6K, 4E-BP, Tor, Rheb, and Foxo proteins regulate cell growth and size in Drosophila and mammals [5,6,29,166–168] (Figure 5).”
• FoxO transcription factors; Regulation by AKT and 14-3-3 proteins. (2011, result): “These studies were consequently confirmed also with DAF-16 and Drosophila FoxO, demonstrating the conservation of this regulatory mechanism through evolution [28–35].”
• Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic cell death. (2007, background): “The intracellular localization of the transcription factor FOXO serves as an in vivo readout of PI3K activity, because it resides in the nucleus under conditions of low PI3K activity and relocalizes to the cytoplasm in response to PI3K-dependent phosphorylation by Akt [35].”
• FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. (2007, neutral): “On the other hand, the FoxO effector arm controls cell number in Drosophila (Junger et al., 2003; Puig et al., 2003), and the FoxO transcription factors mediate some of the growth and survival-promoting effects of AKT signaling in ECs (Potente et al., 2005; Skurk et al., 2004).”
• FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. (2004, neutral): “…to mammals (Junger that unchecked FoxO activity, as found in some chromosomal translocations, results in alveolar rhabdomyosar-et al., 2003; Puig et al., 2003). comas (ARMS) (Xia et al., 2002), an aggressive pediatric cancer thought to arise from the same progenitor cellsFoxOs and Cellular…”