Abstract
Cell death plays a pivotal role in animal development and tissue homeostasis. Dysregulation of this process is associated with a wide variety of human diseases, including developmental and immunological disorders, neurodegenerative diseases and tumors. While the fundamental role of JNK pathway in cell death has been extensively studied, its down-stream regulators and the underlying mechanisms remain largely elusive. From a Drosophila genetic screen, we identified Snail (Sna), a Zinc-finger transcription factor, as a novel modulator of ectopic Egr-induced JNK-mediated cell death. In addition, sna is essential for the physiological function of JNK signaling in development. Our genetic epistasis data suggest that Sna acts downstream of JNK to promote cell death. Mechanistically, JNK signaling triggers dFoxO-dependent transcriptional activation of sna. Thus, our findings not only reveal a novel function and the underlying mechanism of Sna in modulating JNK-mediated cell death, but also provide a potential drug target and therapeutic strategies for JNK signaling-related diseases.
Highlights
Introduction TheSna superfamily of transcription factors has been implicated in a broad spectrum of important biological functions, including mesoderm formation, epithelial–mesenchymal transition (EMT), tumor recurrence, immune regulation, neural differentiation, left–right identity, cell fate, and survival decisions[1,2,3,4]
Depletion of sna suppresses ectopic Egr-induced cell death in development Ectopic expression of the tumor necrosis factor (TNF) ortholog Egr in Drosophila eyes driven by GMR-GAL4 (GMR > Egr) produces a small eye phenotype in the adult stage (Fig. 1b, c)14,15. and triggers apoptotic cell death posterior to the morphogenetic furrow (MF) in third instar eye discs, as revealed by acridine orange (AO) staining that detects dying cells (Fig. 2a, b)[25], and anti-CDcp-1 antibody staining that recognizes the cleaved effector caspase Dcp-1 (Supplementary Fig. 1a, b)[26]
Our genetic epistasis analysis established Sna as a crucial downstream mediator of the Egr-Jun N-terminal Kinase (JNK)-forkhead box O (FoxO) signaling in cell death
Summary
Introduction TheSna superfamily of transcription factors has been implicated in a broad spectrum of important biological functions, including mesoderm formation, epithelial–mesenchymal transition (EMT), tumor recurrence, immune regulation, neural differentiation, left–right identity, cell fate, and survival decisions[1,2,3,4]. Most of the Sna family members share a similar organization, with a evolutionarily conserved C-terminal domain that contains four–six C2H2-type Zinc-fingers for DNA binding, whereas the N terminus with a SNAG (Snail/Gfi) domain harbors the repressor activity[1]. The c-Jun N-terminal Kinase (JNK) signaling is evolutionarily conserved from fruit fly to human, and plays crucial roles in regulating a wide range of cellular activities including proliferation, differentiation and migration, especially cell death[10,11]. This pathway can be triggered by various extrinsic and intrinsic signals, and is mediated through a mitogen-activated protein kinase (MAPK) cascade[12]. Bsk phosphorylates and activates downstream transcription factors including the forkhead box O (FoxO), which modulates UV-induced Bsk-
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