期刊
CANCER CELL
卷 30, 期 2, 页码 290-307出版社
CELL PRESS
DOI: 10.1016/j.ccell.2016.06.023
关键词
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资金
- Spanish Ramon y Cajal fellowship
- Spanish Ministry of Economy and Competitiveness [SAF2010-18518, SAF2013-46089-R]
- WCR [AICR-UK 11-0242]
- Worldwide Cancer Research [11-0242] Funding Source: researchfish
Cancer cells can adapt and survive under low nutrient conditions, but underlying mechanisms remain poorly explored. We demonstrate here that glucose maintains a functional complex between the co-chaperone URI, PP1 gamma, and OGT, the enzyme catalyzing O-GlcNAcylation. Glucose deprivation induces the activation of PKA, which phosphorylates URI at Ser-371, resulting in PP1 gamma release and URI-mediated OGT inhibition. Low OGT activity reduces O-GlcNAcylation and promotes c-MYC degradation to maintain cell survival. In the presence of glucose, PP1 gamma -bound URI increases OGT and c-MYC levels. Accordingly, mice expressing non-phosphorylatable URI (S371A) in hepatocytes exhibit high OGT activity and c-MYC stabilization, accelerating liver tumorigenesis in agreement with c-MYC oncogenic functions. Our work uncovers that URI-regulated OGT confers c-MYC-dependent survival functions in response to glucose fluctuations.
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