Helmholtz Gemeinschaft


aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability

PDF (Original Article) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
[img] Other (Supplementary Material)

Item Type:Article
Title:aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability
Creators Name:Riddell, M. and Nakayama, A. and Hikita, T. and Mirzapourshafiyi, F. and Kawamura, T. and Pasha, A. and Li, M. and Masuzawa, M. and Looso, M. and Steinbacher, T. and Ebnet, K. and Potente, M. and Hirose, T. and Ohno, S. and Fleming, I. and Gattenlöhner, S. and Aung, P.P. and Phung, T. and Yamasaki, O. and Yanagi, T. and Umemura, H. and Nakayama, M.
Abstract:Strict regulation of proliferation is vital for development, whereas unregulated cell proliferation is a fundamental characteristic of cancer. The polarity protein atypical protein kinase C lambda/iota (aPKCλ) is associated with cell proliferation through unknown mechanisms. In endothelial cells, suppression of aPKCλ impairs proliferation despite hyperactivated mitogenic signaling. Here we show that aPKCλ phosphorylates the DNA binding domain of forkhead box O1 (FoxO1) transcription factor, a gatekeeper of endothelial growth. Although mitogenic signaling excludes FoxO1 from the nucleus, consequently increasing c-Myc abundance and proliferation, aPKCλ controls c-Myc expression via FoxO1/miR-34c signaling without affecting its localization. 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. Moreover, FoxO1 phosphorylation at Ser218 and aPKC expression correlates with poor patient prognosis. Our findings may provide a potential therapeutic strategy for treatment of malignant cancers, like angiosarcoma.
Keywords:Cell Line, Cell Proliferation, DNA-Binding Proteins, Endothelial Cells, Forkhead Box Protein O1, Gene Expression Regulation, HEK293 Cells, Hemangiosarcoma, Human Umbilical Vein Endothelial Cells, Isoenzymes, Knockout Mice, MicroRNAs, Phosphorylation, Protein Kinase C, Proto-Oncogene Proteins c-myc, RNA Interference, Small Interfering RNA, Animals, Mice
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:5357
Date:17 December 2018
Official Publication:https://doi.org/10.1038/s41467-018-07739-0
PubMed:View item in PubMed

Repository Staff Only: item control page


Downloads per month over past year

Open Access
MDC Library