VPS34 stimulation of p62 phosphorylation for cancer progression
| العنوان: | VPS34 stimulation of p62 phosphorylation for cancer progression |
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| المؤلفون: | Xingyu Jiang, Yun-Song Yang, Zhaoyun Zhang, Z Qian, Fanghui Sun, Zhaohu Lin, Huijuan Liu, Xuefeng Liu, Kou Xinhui, Lan Jiang, Yan Bao, Xiayu Li |
| المصدر: | Oncogene |
| بيانات النشر: | Springer Science and Business Media LLC, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Small interfering RNA, NF-E2-Related Factor 2, Lipid kinase activity, Biology, Caspase 8, medicine.disease_cause, Mice, 03 medical and health sciences, Neoplasms, Sequestosome-1 Protein, Genetics, medicine, Animals, Humans, Phosphorylation, Molecular Biology, Mice, Inbred BALB C, Gene knockdown, Kinase, fungi, Class III Phosphatidylinositol 3-Kinases, Molecular biology, Cell biology, Protein Kinase C-delta, HEK293 Cells, 030104 developmental biology, Cancer cell, Disease Progression, MCF-7 Cells, Female, Original Article, Carcinogenesis |
| الوصف: | Vps34, a class III PtdIns3 lipid kinase involved in the control of both autophagic and endocytic systems, has been studied extensively in numerous fundamental cellular processes. Accumulating evidence indicates that Vps34 may also contribute to the development and progression of human cancers. However, the mechanism of Vps34 in tumorigenesis remains elusive. Here, we report an unanticipated role of Vps34 in the activation of p62 for cancer development. We identified that Vps34 is a transcriptional activator of p62 through competition of Nrf2 (nuclear factor erythroid 2-related factor 2) for Keap1 binding. Vps34 augments the association of PKC-δ with p62 for its phosphorylation at Serine 349, which leads to positive feedback on the Nrf2-dependent transcription of oncogenes. Additionally, we found that the expression of Vps34 is correlated with the tumorigenic activity of human breast cancer cells. Normally inactive in breast cancer, caspase 8 can cleave Vps34 at residue D285, which directly abolished its lipid kinase activity and dramatically altered cell invasion potential, colony formation, as well as tumorigenesis in orthotopic engraftments in mice. The cleavage at D285 blocks expression of LC3-II, Nrf2 and subsequently, p62, in addition to blocking tumor growth, indicating that the intact structure of Vps34 is essential for its activity. Moreover, either knockout of PKC-δ or knockdown of p62 by small interfering RNA in MCF-7 cells abrogates Vps34-dependent tumor growth. Data presented here suggested that Vps34 stimulates tumor development mainly through PKC-δ- activation of p62. |
| تدمد: | 1476-5594 0950-9232 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fc1fc58de91996d0500ab5d73750501aTest https://doi.org/10.1038/onc.2017.295Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....fc1fc58de91996d0500ab5d73750501a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765594 09509232 |
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