Identification and characterization of novel cell growth regulators in vivo

Abstract

The precise regulation of cell growth and proliferation is mediated by various signaling pathways, whose dysfunction results in defective development and diseases like cancer. Using $\It{Drosophila}$ as a model organism, I identified novel cell growth regulators and investigated their physiological functions in vivo. 1) TOR signaling pathway regulates cell growth and metabolism in response to various nutrient signals by forming complexes with its two different partners, Rictor or Raptor. To distinguish the physiological roles of these complexes, I generated loss-of-function mutants of Rictor and Raptor in $\It{Drosophila}$. As a result, $\It{Rictor-deficient}$ flies showed decreased Akt-dependent tissue hyperplasia and Akt-Ser-505 phosphorylation. Consistently, FOXO-induced apoptosis, which is inhibited by Akt, was enhanced in $\It{Rictor}$ null mutants, indicating that $\It{Rictor}$ is essential for regulating Akt-FOXO signaling module. However, neither S6K-dependent cell growth nor S6K-Thr-398 phosphorylation was affected in $\It{Rictor}$ null mutants. On the other hand, knockdown of Raptor, another TOR binding partner, decreased S6K-Thr-398 phosphorylation and inhibited S6K-induced cell overgrowth. Collectively, these findings strongly suggest that Rictor and Raptor plays pivotal roles in TOR-mediated cell apoptosis and growth control by differentially regulating Akt- and S6K-dependent signaling pathways, respectively. 2) In response to nutrient starvation, bacteria synthesize ppGpp (guanosine 3’,5’-diphosphate) as a signaling alarmone to reduce cell growth and overcome the stress. The synthesis and degradation of ppGpp are mediated by RelA and SpoT enzymes. Although ppGpp signaling is broadly observed in prokaryotes, the identity of its eukaryotic counterparts has remained elusive. Here, I firstly identify functional SpoT homologs in human (hMesh1) and $\It{Drosophila}$ (dMesh1) and reveal their protein structures and biochemical characteristics. Similar to...