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| Item Type: | Article |
|---|---|
| Title: | aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability |
| Creators Name: | Riddell, M., Nakayama, A., Hikita, T., Mirzapourshafiyi, F., Kawamura, T., Pasha, A., Li, M., Masuzawa, M., Looso, M., Steinbacher, T., Ebnet, K., Potente, M., Hirose, T., Ohno, S., Fleming, I., Gattenlöhner, S., Aung, P.P., Phung, T., Yamasaki, O., Yanagi, T., 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 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 9 |
| Number: | 1 |
| Page Range: | 5357 |
| Date: | 17 December 2018 |
| Official Publication: | https://doi.org/10.1038/s41467-018-07739-0 |
| PubMed: | View item in PubMed |
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