A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2
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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-03-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717303200 |
| _version_ | 1819168748448251904 |
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| author | Jing Zhou An-Chi Tien John A. Alberta Scott B. Ficarro Amelie Griveau Yu Sun Janhavee S. Deshpande Joseph D. Card Meghan Morgan-Smith Wojciech Michowski Rintaro Hashizume C. David James Keith L. Ligon William D. Snider Peter Sicinski Jarrod A. Marto David H. Rowitch Charles D. Stiles |
| author_facet | Jing Zhou An-Chi Tien John A. Alberta Scott B. Ficarro Amelie Griveau Yu Sun Janhavee S. Deshpande Joseph D. Card Meghan Morgan-Smith Wojciech Michowski Rintaro Hashizume C. David James Keith L. Ligon William D. Snider Peter Sicinski Jarrod A. Marto David H. Rowitch Charles D. Stiles |
| author_sort | Jing Zhou |
| collection | DOAJ |
| description | 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 3α/β [GSK3α/β], 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. |
| first_indexed | 2024-12-22T19:08:32Z |
| format | Article |
| id | doaj.art-7fb9e82920cf40d1898b5c51de91b9b8 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-22T19:08:32Z |
| publishDate | 2017-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-7fb9e82920cf40d1898b5c51de91b9b82022-12-21T18:15:45ZengElsevierCell Reports2211-12472017-03-0118133167317710.1016/j.celrep.2017.03.003A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2Jing Zhou0An-Chi Tien1John A. Alberta2Scott B. Ficarro3Amelie Griveau4Yu Sun5Janhavee S. Deshpande6Joseph D. Card7Meghan Morgan-Smith8Wojciech Michowski9Rintaro Hashizume10C. David James11Keith L. Ligon12William D. Snider13Peter Sicinski14Jarrod A. Marto15David H. Rowitch16Charles D. Stiles17Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USADepartments of Pediatrics and Neurosurgery, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USADepartment of Neurobiology, Harvard Medical School, Boston, MA 02115, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartments of Pediatrics and Neurosurgery, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USADepartment of Neurobiology, Harvard Medical School, Boston, MA 02115, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USAUNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Neurological Surgery, Northwestern University Feinberg School of Medicine, 300 E. Superior, Chicago, IL 60611, USADepartment of Neurological Surgery, Northwestern University Feinberg School of Medicine, 300 E. Superior, Chicago, IL 60611, USADepartment of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USAUNC Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartments of Pediatrics and Neurosurgery, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143, USADepartment of Neurobiology, Harvard Medical School, Boston, MA 02115, USADuring 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 3α/β [GSK3α/β], 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.http://www.sciencedirect.com/science/article/pii/S2211124717303200Olig2phosphorylationprotein kinasecyclin-dependent kinaseCDKcasein kinase 2CK2glycogen synthase kinase 3GSK3neural progenitor cellsNPCsglioma |
| spellingShingle | Jing Zhou An-Chi Tien John A. Alberta Scott B. Ficarro Amelie Griveau Yu Sun Janhavee S. Deshpande Joseph D. Card Meghan Morgan-Smith Wojciech Michowski Rintaro Hashizume C. David James Keith L. Ligon William D. Snider Peter Sicinski Jarrod A. Marto David H. Rowitch Charles D. Stiles A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2 Cell Reports Olig2 phosphorylation protein kinase cyclin-dependent kinase CDK casein kinase 2 CK2 glycogen synthase kinase 3 GSK3 neural progenitor cells NPCs glioma |
| title | A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2 |
| title_full | A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2 |
| title_fullStr | A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2 |
| title_full_unstemmed | A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2 |
| title_short | A Sequentially Priming Phosphorylation Cascade Activates the Gliomagenic Transcription Factor Olig2 |
| title_sort | sequentially priming phosphorylation cascade activates the gliomagenic transcription factor olig2 |
| topic | Olig2 phosphorylation protein kinase cyclin-dependent kinase CDK casein kinase 2 CK2 glycogen synthase kinase 3 GSK3 neural progenitor cells NPCs glioma |
| url | http://www.sciencedirect.com/science/article/pii/S2211124717303200 |
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