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

Meghan Riddell, Akiko Nakayama, Takao Hikita, Fatemeh Mirzapourshafiyi, Takuji Kawamura, Ayesha Pasha, Mengnan Li, Mikio Masuzawa, Mario Looso, Tim Steinbacher, Klaus Ebnet, Michael Potente, Tomonori Hirose, Shigeo Ohno, Ingrid Fleming, Stefan Gattenlöhner, Phyu P. Aung, Thuy Phung, Osamu Yamasaki, Teruki Yanagi, Hiroshi Umemura and Masanori Nakayama ()
Additional contact information
Meghan Riddell: Max Planck Institute for Heart and Lung Research
Akiko Nakayama: Max Planck Institute for Heart and Lung Research
Takao Hikita: Max Planck Institute for Heart and Lung Research
Fatemeh Mirzapourshafiyi: Max Planck Institute for Heart and Lung Research
Takuji Kawamura: Max Planck Institute for Heart and Lung Research
Ayesha Pasha: Max Planck Institute for Heart and Lung Research
Mengnan Li: Max Planck Institute for Heart and Lung Research
Mikio Masuzawa: Kitasato University
Mario Looso: Max Planck Institute for Heart and Lung Research
Tim Steinbacher: University of Münster
Klaus Ebnet: University of Münster
Michael Potente: Max Planck Institute for Heart and Lung Research
Tomonori Hirose: Yokohama City University School of Medicine
Shigeo Ohno: Yokohama City University School of Medicine
Ingrid Fleming: Goethe University
Stefan Gattenlöhner: Justus-Liebig-University Giessen
Phyu P. Aung: M.D. Anderson Cancer Center
Thuy Phung: Texas Children’s Hospital
Osamu Yamasaki: School of Medicine
Teruki Yanagi: Hokkaido University Graduate School of Medicine
Hiroshi Umemura: School of Medicine
Masanori Nakayama: Max Planck Institute for Heart and Lung Research

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07739-0

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