mTOR Signaling Upregulates CDC6 via Suppressing miR-3178 and Promotes the Loading of DNA Replication Helicase
| Autor: | Peter J. Houghton, Zhengfu He, Changxian Shen, Xiaoliang Xiang, Shenghua Li, Megan Halloran, Terence M. Williams, Xianjin Wu, Linlin Yang, Xing Hu |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cell Survival lcsh:Medicine Cell Cycle Proteins Biology mTORC2 Article 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Proliferating Cell Nuclear Antigen Rhabdomyosarcoma Humans lcsh:Science PI3K/AKT/mTOR pathway Multidisciplinary Minichromosome Maintenance Proteins TOR Serine-Threonine Kinases lcsh:R DNA replication Nuclear Proteins Oncogenes DNA replication origin Up-Regulation Chromatin Proliferating cell nuclear antigen Cell biology Gene Expression Regulation Neoplastic MicroRNAs 030104 developmental biology Licensing factor Checkpoint signalling biology.protein Replisome lcsh:Q 030217 neurology & neurosurgery HeLa Cells Signal Transduction |
| Zdroj: | Scientific Reports, Vol 9, Iss 1, Pp 1-8 (2019) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-019-46052-8 |
| Popis: | mTOR signaling pathway is deregulated in most cancers and uncontrolled cell cycle progression is a hallmark of cancer cell. However, the precise molecular mechanisms of the regulation of DNA replication and chromatin metabolism by mTOR signaling are largely unknown. We herein report that mTOR signaling promotes the loading of MCM2-7 helicase onto chromatin and upregulates DNA replication licensing factor CDC6. Pharmacological inhibition of mTOR kinase resulted in CHK1 checkpoint activation and decreased MCM2-7 replication helicase and PCNA associated with chromatins. Further pharmacological and genetic studies demonstrated CDC6 is positively controlled by mTORC1-S6K1 and mTORC2 signaling. miRNA screening revealed mTOR signaling suppresses miR-3178 thereby upregulating CDC6. Analysis of TCGA data found that CDC6 is overexpressed in most cancers and associates with the poor survival of cancer patients. Our findings suggest that mTOR signaling may control DNA replication origin licensing and replisome stability thereby cell cycle progression through CDC6 regulation. |
| Databáze: | OpenAIRE |
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