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aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability
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, su...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297234/ https://www.ncbi.nlm.nih.gov/pubmed/30559384 http://dx.doi.org/10.1038/s41467-018-07739-0 |
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author | Riddell, Meghan Nakayama, Akiko Hikita, Takao Mirzapourshafiyi, Fatemeh Kawamura, Takuji Pasha, Ayesha Li, Mengnan Masuzawa, Mikio Looso, Mario Steinbacher, Tim Ebnet, Klaus Potente, Michael Hirose, Tomonori Ohno, Shigeo Fleming, Ingrid Gattenlöhner, Stefan Aung, Phyu P. Phung, Thuy Yamasaki, Osamu Yanagi, Teruki Umemura, Hiroshi Nakayama, Masanori |
author_facet | Riddell, Meghan Nakayama, Akiko Hikita, Takao Mirzapourshafiyi, Fatemeh Kawamura, Takuji Pasha, Ayesha Li, Mengnan Masuzawa, Mikio Looso, Mario Steinbacher, Tim Ebnet, Klaus Potente, Michael Hirose, Tomonori Ohno, Shigeo Fleming, Ingrid Gattenlöhner, Stefan Aung, Phyu P. Phung, Thuy Yamasaki, Osamu Yanagi, Teruki Umemura, Hiroshi Nakayama, Masanori |
author_sort | Riddell, Meghan |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6297234 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-62972342018-12-19 aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability Riddell, Meghan Nakayama, Akiko Hikita, Takao Mirzapourshafiyi, Fatemeh Kawamura, Takuji Pasha, Ayesha Li, Mengnan Masuzawa, Mikio Looso, Mario Steinbacher, Tim Ebnet, Klaus Potente, Michael Hirose, Tomonori Ohno, Shigeo Fleming, Ingrid Gattenlöhner, Stefan Aung, Phyu P. Phung, Thuy Yamasaki, Osamu Yanagi, Teruki Umemura, Hiroshi Nakayama, Masanori Nat Commun Article 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. Nature Publishing Group UK 2018-12-17 /pmc/articles/PMC6297234/ /pubmed/30559384 http://dx.doi.org/10.1038/s41467-018-07739-0 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Riddell, Meghan Nakayama, Akiko Hikita, Takao Mirzapourshafiyi, Fatemeh Kawamura, Takuji Pasha, Ayesha Li, Mengnan Masuzawa, Mikio Looso, Mario Steinbacher, Tim Ebnet, Klaus Potente, Michael Hirose, Tomonori Ohno, Shigeo Fleming, Ingrid Gattenlöhner, Stefan Aung, Phyu P. Phung, Thuy Yamasaki, Osamu Yanagi, Teruki Umemura, Hiroshi Nakayama, Masanori aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability |
title | aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability |
title_full | aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability |
title_fullStr | aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability |
title_full_unstemmed | aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability |
title_short | aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability |
title_sort | apkc controls endothelial growth by modulating c-myc via foxo1 dna-binding ability |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297234/ https://www.ncbi.nlm.nih.gov/pubmed/30559384 http://dx.doi.org/10.1038/s41467-018-07739-0 |
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