title: Notch-dependent expression of the archipelago ubiquitin ligase subunit in the Drosophila eye.
abstract: archipelago (ago)/Fbw7 encodes a conserved protein that functions as the substrate-receptor component of a polyubiquitin ligase that suppresses tissue growth in flies and tumorigenesis in vertebrates. Ago/Fbw7 targets multiple proteins for degradation, including the G1-S regulator Cyclin E and the oncoprotein dMyc/c-Myc. Despite prominent roles in growth control, little is known about the signals that regulate Ago/Fbw7 abundance in developing tissues. Here we use the Drosophila eye as a model to identify developmental signals that regulate ago expression. We find that expression of ago mRNA and protein is induced by passage of the morphogenetic furrow (MF) and identify the hedgehog (hh) and Notch (N) pathways as elements of this inductive mechanism. Cells mutant for N pathway components, or hh-defective cells that express reduced levels of the Notch ligand Delta, fail to upregulate ago transcription in the region of the MF; reciprocally, ectopic N activation in eye discs induces expression of ago mRNA. A fragment of the ago promoter that contains consensus binding sites for the N pathway transcription factor Su(H) is bound by Su(H) and confers N-inducibility in cultured cells. The failure to upregulate ago in N pathway mutant cells correlates with accumulation of the SCF-Ago target Cyclin E in the area of the MF, and this is rescued by re-expression of ago. These data suggest a model in which N acts through ago to restrict levels of the pro-mitotic factor Cyclin E. This N-Ago-Cyclin E link represents a significant new cell cycle regulatory mechanism in the developing eye.
authors.affiliation: Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Nicholson
authors.forename: Brandon N
authors.initials: BN
authors.lastname: Nicolay
authors.forename: Maxim V
authors.initials: MV
authors.lastname: Frolov
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Moberg
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D002453:Cell Cycle; D019927:Cyclin E / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics* / Q000254:growth & development* / Q000378:metabolism; D005123:Eye / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D044783:F-Box Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D017344:Genes, Insect; D053823:Hedgehog Proteins / Q000235:genetics; D009154:Mutation; D011401:Promoter Regions, Genetic; D021122:Protein Subunits; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D019927:Cyclin E; D017931:DNA Primers; D029721:Drosophila Proteins; D044783:F-Box Proteins; D053823:Hedgehog Proteins; C497759:N protein, Drosophila; D021122:Protein Subunits; D012333:RNA, Messenger; D051880:Receptors, Notch; C488876:ago protein, Drosophila; C077245:hh protein, Drosophila; D044767:Ubiquitin-Protein Ligases