Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway.
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.
Puig
Oscar
O
Howard Hughes Medical Institute and Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
Marr
Michael T
MT
Ruhf
M Laure
ML
Tjian
Robert
R
D000595:Amino Acid Sequence; D000818:Animals; D002452:Cell Count; D002455:Cell Division / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004330:Drosophila / Q000166:cytology / Q000254:growth & development*; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors; D025461:Feedback, Physiological; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D009025:Morpholines / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D002867:Chromones; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; D019476:Insect Proteins; D007328:Insulin; D009025:Morpholines; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D011972:Receptor, Insulin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt