RRC ID 52872
著者 Katsukawa M, Ohsawa S, Zhang L, Yan Y, Igaki T.
タイトル Serpin Facilitates Tumor-Suppressive Cell Competition by Blocking Toll-Mediated Yki Activation in Drosophila.
ジャーナル Curr Biol
Abstract Normal epithelial tissue exerts an intrinsic tumor-suppressive effect against oncogenically transformed cells. In Drosophila imaginal epithelium, clones of oncogenic polarity-deficient cells mutant for scribble (scrib) or discs large (dlg) are eliminated by cell competition when surrounded by wild-type cells. Here, through a genetic screen in Drosophila, we identify Serpin5 (Spn5), a secreted negative regulator of Toll signaling, as a crucial factor for epithelial cells to eliminate scrib mutant clones from epithelium. Downregulation of Spn5 in wild-type cells leads to elevation of Toll signaling in neighboring scrib cells. Strikingly, forced activation of Toll signaling or Toll-related receptor (TRR) signaling in scrib clones transforms scrib cells from losers to supercompetitors, resulting in tumorous overgrowth of mutant clones. Mechanistically, Toll activation in scrib clones leads to c-Jun N-terminal kinase (JNK) activation and F-actin accumulation, which cause strong activation of the Hippo pathway effector Yorkie that blocks cell death and promotes cell proliferation. Our data suggest that Spn5 secreted from normal epithelial cells acts as a component of the extracellular surveillance system that facilitates elimination of pre-malignant cells from epithelium.
巻・号 28(11)
ページ 1756-1767.e6
公開日 2018-6-4
DOI 10.1016/j.cub.2018.04.022
PII S0960-9822(18)30450-0
PMID 29804808
MeSH Animals Drosophila Proteins / genetics* Drosophila Proteins / metabolism Drosophila melanogaster / genetics* Drosophila melanogaster / metabolism Epithelial Cells / metabolism Gene Expression Regulation / physiology* Membrane Proteins / metabolism Nuclear Proteins / genetics Nuclear Proteins / metabolism Serpins / genetics* Serpins / metabolism Signal Transduction / genetics* Toll-Like Receptors / genetics Toll-Like Receptors / physiology* Trans-Activators / genetics Trans-Activators / metabolism YAP-Signaling Proteins
IF 9.601
引用数 16
リソース情報
ショウジョウバエ HMS01371 4005R-2 HMS03159 HMS02693 HMS22392 HMS21559