期刊
CELL REPORTS
卷 18, 期 13, 页码 3167-3177出版社
CELL PRESS
DOI: 10.1016/j.celrep.2017.03.003
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资金
- American Brain Tumor Association
- American Association for Cancer Research(AACR)
- Basic Cancer Research
- NIH [NS057727, NS040511]
- DanaFarber Strategic Research Initiative
- Howard Hughes Medical Institute
- Kids' Brain Tumor Cure Foundation
- Medical Research Council [MC_PC_12009] Funding Source: researchfish
During development of the vertebrate CNS, the basic helix-loop-helix (bHLH) transcription factor Olig2 sustains replication competence of progenitor cells that give rise to neurons and oligodendrocytes. A pathological counterpart of this developmental function is seen in human glioma, wherein Olig2 is required for maintenance of stem-like cells that drive tumor growth. The mitogenic/gliomagenic functions of Olig2 are regulated by phosphorylation of a triple serine motif (S10, S13, and S14) in the amino terminus. Here, we identify a set of three serine/threonine protein kinases (glycogen synthase kinase 3 alpha/beta [GSK3 alpha/beta], casein kinase 2 [CK2], and cyclin-dependent kinases 1/2 [CDK1/2]) that are, collectively, both necessary and sufficient to phosphorylate the triple serine motif. We show that phosphorylation of the motif itself serves as a template to prime phosphorylation of additional serines and creates a highly charged acid blob in the amino terminus of Olig2. Finally, we show that small molecule inhibitors of this forward-feeding phosphorylation cascade have potential as glioma therapeutics.
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