Dataset Information

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

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 (aPKC lambda) is associated with cell proliferation through unknown mechanisms. In endothelial cells, suppression of aPKC lambda impairs proliferation despite hyperactivated mitogenic signaling. Here we show that aPKC lambda 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, aPKC lambda 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 new therapeutic strategy for treatment of malignant cancers, like angiosarcoma.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Scientific Service Group Biomolecular Mass Spectrometry

LAB HEAD: Masanori Nakayama

PROVIDER: PXD011595 | Pride | 2019-11-12

REPOSITORIES: Pride

ACCESS DATA

Publications

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

Riddell Meghan M Nakayama Akiko A Hikita Takao T Mirzapourshafiyi Fatemeh F Kawamura Takuji T Pasha Ayesha A Li Mengnan M Masuzawa Mikio M Looso Mario M Steinbacher Tim T Ebnet Klaus K Potente Michael M Hirose Tomonori T Ohno Shigeo S Fleming Ingrid I Gattenlöhner Stefan S Aung Phyu P PP Phung Thuy T Yamasaki Osamu O Yanagi Teruki T Umemura Hiroshi H Nakayama Masanori M

Nature communications 20181217 1

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 ga ...[more]

PMID: 30559384

Similar Datasets

Project description:Melanocytes within benign human nevi are the paradigm for tumor suppressive senescent cells in a pre-malignant neoplasm. These cells typically contain mutations in either the BRAF or N-RAS oncogene and express markers of senescence, including p16. However, a nevus can contain 10s to 100s of thousands of clonal melanocytes and approximately 20-30% of melanoma are thought to arise in association with a pre-existing nevus. Neither observation is indicative of fail-safe senescence-associated proliferation arrest and tumor suppression. We set out to better understand the status of nevus melanocytes. Proliferation-promoting Wnt target genes, such as cyclin D1 and c-myc, were repressed in oncogene-induced senescent melanocytes in vitro, and repression of Wnt signaling in these cells induced a senescent-like state. In contrast, cyclin D1 and c-myc were expressed in many melanocytes of human benign nevi. Specifically, activated Wnt signalling in nevi correlated inversely with nevus maturation, an established dermatopathological correlate of clinical benignancy. Single cell analyses of lone epidermal melanocytes and nevus melanocytes showed that expression of proliferation-promoting Wnt targets correlates with prior proliferative expansion of p16-expressing nevus melanocytes. In a mouse model, activation of Wnt signaling delayed, but did not bypass, senescence of oncogene-expressing melanocytes, leading to massive accumulation of proliferation-arrested, p16-positive non-malignant melanocytes. We conclude that clonal hyperproliferation of oncogene-expressing melanocytes to form a nevus is facilitated by transient delay of senescence due to activated Wnt signaling. The observation that activation of Wnt signaling correlates inversely with nevus maturation, an indicator of clinical benignancy, supports the notion that persistent destabilization of senescence by Wnt signaling contributes to the malignant potential of nevi. We used RNA-Seq to detail the global programme of gene expression in human melanoma cell lines

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure