RRC ID 57466
著者 Li M, Sun S, Priest J, Bi X, Fan Y.
タイトル Characterization of TNF-induced cell death in Drosophila reveals caspase- and JNK-dependent necrosis and its role in tumor suppression.
ジャーナル Cell Death Dis
Abstract Tumor-necrosis factor (TNF) and its superfamily members are pleiotropic cytokines. Activation of TNF can lead to distinct cellular outcomes including inflammation, cell survival, and different forms of cell death, such as apoptosis and necrosis in a context-dependent manner. However, our understanding of what determines the versatile functions of TNF is far from complete. Here, we examined the molecular mechanisms that distinguish the forms of cell death induced by Eiger (Egr), the sole homolog of TNF in Drosophila. We show that expression of Egr in the developing Drosophila eye simultaneously induces apoptosis and apoptosis-independent developmental defects indicated by cellular disorganization, both of which rely on the c-Jun N-terminal kinase (JNK) signaling activity. Intriguingly, when effector caspases DrICE and Dcp-1 are defective or inhibited, expression of Egr triggers necrosis which is characterized by loss of cell membrane integrity, translucent cytoplasm, and aggregation of cellular organelles. Moreover, such Egr-induced necrosis depends on the catalytic activity of the initiator caspase Dronc and the input from JNK signaling but is independent of their roles in apoptosis. Further mosaic analysis with mutants of scribble (scrib), an evolutionarily conserved tumor suppressor gene regulating cell polarity, suggests that Egr/JNK-mediated apoptosis and necrosis establish a two-layered defense system to inhibit the oncogenic growth of scrib mutant cells. Together, we have identified caspase- and JNK-dependent mechanisms underlying Egr-induced apoptosis versus necrosis and their fail-safe roles in tumor suppression in an intact organism in vivo.
巻・号 10(8)
ページ 613
公開日 2019-8-14
DOI 10.1038/s41419-019-1862-0
PII 10.1038/s41419-019-1862-0
PMID 31409797
PMC PMC6692325
MeSH Animals Apoptosis / genetics Caspases / genetics* Cell Polarity / genetics Disease Models, Animal Drosophila Proteins / genetics* Drosophila melanogaster / genetics Gene Expression Regulation / genetics Genes, Tumor Suppressor* Humans JNK Mitogen-Activated Protein Kinases / genetics MAP Kinase Signaling System / genetics Membrane Proteins / genetics* Necrosis / genetics Necrosis / pathology Neoplasms / genetics Neoplasms / pathology Tumor Necrosis Factor-alpha / genetics
IF 5.959
引用数 2
リソース情報
ショウジョウバエ 7788R-1 7788R-2 5370R-2