Characterization of tumor suppressor LKB1 signaling pathway in vivo

Abstract

LKB1 is a serine/threonine kinase that functions as a master tumor suppressor in the small intestine. Although numerous molecular and biochemical studies have implicated LKB1 in a variety function of cellular processes, little is known about the tumor suppressing mechanism of LKB1 in vivo. Therefore, I performed genetic modifier screening in Drosophila to discover the novel proteins involved in tumor suppressor LKB1 signaling pathway in vivo. Subsequently, I identified Silnoon (Sln) as a novel LKB1-interacting gene, which is a monocarboxylate transporter (MCT) mediating the influx of extra-cellular butyrate. Surprisingly, Sln induces ectopic apoptosis, which is enhanced by co-expression of LKB1 as well as butyrate treatment. In contrast, downregulation of Sln suppressed LKB1-dependent apoptosis and caused a drastic brain hyperplasia phenotype as observed in the LKB1-null mutant. Moreover, ectopic expression of Sln was sufficient to suppress the brain hyperplasia phenotype of LKB1-null mutant, demonstrating that Sln is a downstream effector of the LKB1 signaling pathway. Finally, I showed that LKB1 kinase activity affects the subcellular localization of Sln during eye morphogenesis. Since some monocarboxylate transporters are involved in the cancer development as a tumor, I suggest a plausible synapse between the two tumor suppressing mechanisms, LKB1 and MCT, which however were known be unlinked.