Notch-dependent expression of the archipelago ubiquitin ligase subunit in the Drosophila eye

Abstract

SUMMARYarchipelago (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.

TheDrosophilaubiquitin-specific protease Puffyeye regulates dMyc-mediated growth

“…Previous studies have shown that multiple signaling pathways regulate Ago and Fbw7 expression and activity (Nicholson et al, 2011). Here, we find that Ago levels are increased upon dMyc, as well as upon Puf overexpression.…”

Genetic mapping of male pheromone response in the European corn borer identifies candidate genes regulating neurogenesis

“…The second likely candidate is a gene with LIM and homeobox domains characteristic of many transcription factors that has also been described as a neural-patterning gene in several organisms [i.e., Drosophila, mice, and Caenorhabditis elegans (50)]. The third likely candidate is archipelago (ago), which encodes an F-box protein and part of a ubiquitin ligase complex that interacts with the Notch signaling pathway and suppresses tissue growth in flies and tumor development in vertebrates (51,52). Mutations in the fourth likely candidate, bab, have many consequences, including disordered arrangements of eggs in the ovaries in D. melanogaster (53).…”

Signaling Pathways that Control Cell Proliferation

“…Mitogen signaling can also influence the activity of FBW7 itself. In mammalian cells, activated Ras increases cyclin E levels by inhibiting binding of cyclin E to FBW7 , and Notch and Hedgehog signaling suppresses cyclin E accumulation by inducing FBW7 expression in Drosophila eye imaginal discs (Nicholson et al 2011). Therefore, both oncogenic and developmental signals can control the level of cyclin E protein by regulating components of the E3 ubiquitin ligase that targets cyclin E for destruction (Fig.…”