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Rab5-regulated endocytosis plays a crucial role in apical extrusion of transformed cells

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Title: Rab5-regulated endocytosis plays a crucial role in apical extrusion of transformed cells
Authors: Saitoh, Sayaka Browse this author
Maruyama, Takeshi Browse this author
Yako, Yuta Browse this author
Kajita, Mihoko Browse this author →KAKEN DB
Fujioka, Yoichiro Browse this author
Ohba, Yusuke Browse this author →KAKEN DB
Kasai, Nobuhiro Browse this author
Sugama, Natsu Browse this author
Kon, Shunsuke Browse this author →KAKEN DB
Ishikawa, Susumu Browse this author
Hayashi, Takashi Browse this author
Yamazaki, Tomohiro Browse this author
Tada, Masazumi Browse this author
Fujita, Yasuyuki Browse this author →KAKEN DB
Keywords: cell competition
apical extrusion
Issue Date: 21-Mar-2017
Publisher: National Academy of Sciences
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 114
Issue: 12
Start Page: E2327
End Page: E2336
Publisher DOI: 10.1073/pnas.1602349114
Abstract: Newly emerging transformed cells are often eliminated from epithelial tissues. Recent studies have revealed that this cancer-preventive process involves the interaction with the surrounding normal epithelial cells; however, the molecular mechanisms underlying this phenomenon remain largely unknown. In this study, using mammalian cell culture and zebrafish embryo systems, we have elucidated the functional involvement of endocytosis in the elimination of RasV12-transformed cells. First, we show that Rab5, a crucial regulator of endocytosis, is accumulated in RasV12-transformed cells that are surrounded by normal epithelial cells, which is accompanied by up-regulation of clathrin-dependent endocytosis. Addition of chlorpromazine or coexpression of a dominant-negative mutant of Rab5 suppresses apical extrusion of RasV12 cells from the epithelium. We also show in zebrafish embryos that Rab5 plays an important role in the elimination of transformed cells from the enveloping layer epithelium. In addition, Rab5-mediated endocytosis of E-cadherin is enhanced at the boundary between normal and RasV12 cells. Rab5 functions upstream of epithelial protein lost in neoplasm (EPLIN), which plays a positive role in apical extrusion of RasV12 cells by regulating protein kinase A. Furthermore, we have revealed that epithelial defense against cancer (EDAC) from normal epithelial cells substantially impacts on Rab5 accumulation in the neighboring transformed cells. This report demonstrates that Rab5-mediated endocytosis is a crucial regulator for the competitive interaction between normal and transformed epithelial cells in mammals.
Type: article (author version)
Appears in Collections:遺伝子病制御研究所 (Institute for Genetic Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 藤田 恭之

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