Light and dark sides of polarity proteins

演題

Light and dark sides of polarity proteins

講演者

中山　雅敬　博士 （Max-Planck-Institute for Heart and Lung Research ）

使用言語

English

日時

2017年7月24日(月曜日) 11：00～12：00

場所

大セミナー室

内容

Cell proliferation is controlled not only by growth factors, but also by polarization. Disrupted polarity is a hallmark of excessive cell expansion, however a molecular mechanism remains elusive. Polarity protein atypical protein kinase C lambda/iota (aPKC l), is associated with proliferation and is an oncogene. In endothelia, suppression of aPKC l impairs proliferation despite hyper-activated vascular endothelial growth factor (VEGF) signaling (1, 2). Here we show that aPKC l phosphorylates the DNA binding domain of forkhead box O1 (FoxO1) transcription factor, a gatekeeper of endothelial growth. Although VEGF signaling is known to exclude FoxO1 from the nucleus, consequently increasing c-Myc abundance and proliferation, aPKC l controls c-Myc transcription via FoxO1 without affecting its localization in vivo. We find this pathway is strongly activated in the malignant vascular sarcoma, angiosarcoma, and aPKC inhibition reduces c-Myc expression and proliferation of angiosarcoma cells. Additionally, we confirm phosphorylation of FoxO1 by aPKC in more than 70% of the angiosarcoma patients. While median survival time of phospho-FoxO1 positive patients is 14 months, that of negative patients is 37 months. Our findings may provide a new therapeutic strategy for treatment of malignant cancers, such as angiosarcoma.

問合せ先

神経システム生物学
稲垣 直之 (ninagaki@bs.naist.jp)