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Nat Commun. 2018 Dec 17;9(1):5357. doi: 10.1038/s41467-018-07739-0.

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

Author information

1
Laboratory for Cell Polarity and Organogenesis, Max Planck Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany.
2
Department of Pharmacology, Max Planck Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany.
3
Department of Molecular Diagnostics, School of Allied Health Sciences, Kitasato University, Kanagawa, 252-0374, Japan.
4
Bioinformatics Service Group, Max Planck Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany.
5
Institute-Associated Research Group: Cell Adhesion and Cell Polarity, Institute of Medical Biochemistry, ZMBE, University of Münster, 48149, Münster, Germany.
6
Angiogenesis and Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany.
7
Department of Molecular Biology, Yokohama City University School of Medicine, Yokohama, 236-0004, Japan.
8
Institute for Vascular Signaling, Centre for Molecular Medicine, Goethe University, 60596, Frankfurt, Germany.
9
Institute of Pathology, University Hospital, Justus-Liebig-University Giessen, 35392, Giessen, Germany.
10
Department of Pathology University of Texas, M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
11
Department of Pathology & Immunology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, 77030, USA.
12
Department of Dermatology, Okayama University, School of Medicine, Okayama, 700-8558, Japan.
13
Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, 060-8638, Japan.
14
Laboratory for Cell Polarity and Organogenesis, Max Planck Institute for Heart and Lung Research, 61231, Bad Nauheim, Germany. masanori.nakayama@mpi-bn.mpg.de.

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.

PMID:
30559384
PMCID:
PMC6297234
DOI:
10.1038/s41467-018-07739-0
[Indexed for MEDLINE]
Free PMC Article

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