Tumor Suppressor CYLD Regulates JNK-Induced Cell Death in Drosophila

Abstract

CYLD encodes a tumor suppressor that is mutated in familial cylindromatosis. Despite biochemical and cell culture studies, the physiological functions of CYLD in animal development and tumorigenesis remain poorly understood. To address these questions, we generated Drosophila CYLD (dCYLD) mutant and transgenic flies expressing wild-type and mutant dCYLD proteins. Here we show that dCYLD is essential for JNK-dependent oxidative stress resistance and normal lifespan. Furthermore, dCYLD regulates TNF-induced JNK activation and cell death through dTRAF2, which acts downstream of the TNF receptor Wengen and upstream of the JNKK kinase dTAK1. We show that dCYLD encodes a deubiquitinating enzyme that deubiquitinates dTRAF2 and prevents dTRAF2 from ubiquitin-mediated proteolytic degradation. These data provide a molecular mechanism for the tumor suppressor function of this evolutionary conserved molecule by indicating that dCYLD plays a critical role in modulating TNF-JNK-mediated cell death.

Drosophila Smt3 negatively regulates JNK signaling through sequestering Hipk in the nucleus

“…To further investigate the relationship between Hipk action and the Smt3 status for their roles in JNK activation, we used the sensitive eye phenotype for our investigation. As shown previously, the severity of rough eyes reflects the strength of JNK-dependent apoptosis (Igaki et al, 2002;Moreno et al, 2002;Tiwari and Roy, 2009;Xue et al, 2007). Here, we simultaneously expressed UAS-hipk and smt3-RNAi constructs under the control of GMR-Gal4.…”

“…In Drosophila, JNK is encoded by the gene basket (bsk). The upstream regulators of Bsk include a series of kinases that form a signaling cascade (Stronach and Perrimon, 2002;Takatsu et al, 2000;Tateno et al, 2000;Xue et al, 2007). MSN, a MAPK kinase kinase kinase (MAPKKKK) receives signals from cell surface receptors and initiates this signaling cascade (Liu et al, 1999;Xue et al, 2007).…”

“…The upstream regulators of Bsk include a series of kinases that form a signaling cascade (Stronach and Perrimon, 2002;Takatsu et al, 2000;Tateno et al, 2000;Xue et al, 2007). MSN, a MAPK kinase kinase kinase (MAPKKKK) receives signals from cell surface receptors and initiates this signaling cascade (Liu et al, 1999;Xue et al, 2007). While the main signaling pathway transmits from MSN to JNK hierarchically, other factors connected to this main pathway also function in fine-tuning of the signaling, especially in activating or repressing the JNK activity (Chen et al, 2002;Neisch et al, 2010;Shanley et al, 2001;Yang et al, 1997).…”

NOPO modulates Egr-induced JNK-independent cell death in Drosophila

“…We propose a model that the Ben-dUEV1a E2 complex constitutes a molecular switch which, by choosing dTRAF2 or NOPO as its E3 partner, transduces Egr-induced cell death signaling through two independent pathways, one mediated by dTRAF2-JNK and another by NOPO-caspase ( Figure 4I). [8], UASBen T8 [28], dTAK1 1 [29] were previously described.…”

“…Upon phosphorylation by the mitogen-activated protein (MAP) kinase cascade, JNK translocates into the nucleus, phosphorylates and activates transcription factors such as Jun and Fos, and finally leads to caspase-mediated apoptosis [4,5]. This signaling pathway is highly conserved in Drosophila, in which the TNF orthlog Eiger (Egr) triggers cell death through its receptor Wengen (Wgn), the TNF receptor-associated factor 2 (dTRAF2), the JNKK kinase dTAK1, the JNK kinase Hemipterous (Hep) and Basket (Bsk) that encodes the Drosophila JNK [6][7][8]. Although considerable progress has been made to characterize the molecular mechanism underlying cell death induced by TNF-JNK signaling [9], whether caspases are involved in this process has remained controversial [6,7].…”