Abstract
Appropriate expression of growth-regulatory genes is essential to ensure normal animal development and to prevent diseases like cancer. Gene regulation at the levels of transcription and translational initiation mediated by the Hippo and Insulin signaling pathways and by the TORC1 complex, respectively, has been well documented. Whether translational control mediated by RNA-binding proteins contributes to the regulation of cellular growth is less clear. Here, we identify Lingerer (Lig), an UBA domain-containing protein, as growth suppressor that associates with the RNA-binding proteins Fragile X mental retardation protein 1 (FMR1) and Caprin (Capr) and directly interacts with and regulates the RNA-binding protein Rasputin (Rin) in Drosophila melanogaster. lig mutant organs overgrow due to increased proliferation, and a reporter for the JAK/STAT signaling pathway is upregulated in a lig mutant situation. rin, Capr or FMR1 in combination as double mutants, but not the respective single mutants, display lig like phenotypes, implicating a redundant function of Rin, Capr and FMR1 in growth control in epithelial tissues. Thus, Lig regulates cell proliferation during development in concert with Rin, Capr and FMR1.
Highlights
Understanding how cells and organs control their growth is a major endeavor in developmental biology
This regulation is achieved at different molecular levels like transcription, translation initiation, and translational regulation
We describe Lingerer (Lig), an UBA domain-containing protein, as a new growth suppressor that associates with the three RNA-binding proteins Fragile X mental retardation protein 1 (FMR1), Rasputin (Rin) and cytoplasmic activation/proliferation associated protein (Caprin) (Capr)
Summary
Understanding how cells and organs control their growth is a major endeavor in developmental biology. Increasing evidence indicates that RNA-binding proteins like Fragile X mental retardation 1 protein (FMR1), mammalian cytoplasmic activation/proliferation associated protein (Caprin) and mammalian Ras-GTPase activating protein SH3 domain binding protein (G3BP) regulate growth and growth factors at the translational level [2,3,4,5]. FMR1 knockout mice display increased proliferation of adult progenitor/stem cells in two-month-old mice, probably caused by increased protein levels of CDK4, Cyclin D1, and GSK3b as a result of missing translational regulation [2]. In Drosophila, FMR1 maintains germline stem cells in ovaries using the miRNA bantam [6], and brains of FMR1 mutants display increased neuroblast proliferation rates with altered Cyclin E levels [7]. It was demonstrated that FMR1 associates with the RNA-binding protein Caprin in mice [8] and flies [9] to cooperate in binding to the same mRNA targets (at least in flies [9])
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