 |
 |
GEO help: Mouse over screen elements for information. |
|
| Status |
Public on Sep 13, 2016 |
| Title |
RNA-Seq analysis of human medulloblastoma cell lines with SOX9 overexpression |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
SOX9 is a master transcription factor that regulates development and stem cell programs. However, its potential oncogenic activity and regulatory mechanisms that control SOX9 protein stability are poorly understood. Here we show that SOX9 is a substrate of FBW7, a tumor suppressor and a SCF (Skp1-Cul1-F-box)-type ubiquitin ligase. FBW7 recognizes a conserved degron surrounding threonine 236 (T236) in SOX9 that is phosphorylated by GSK3 kinase. Specifically, FBW7-alpha targets T236-phosphorylated SOX9 for ubiquitylation and proteasomal degradation. Further, we demonstrate that FBW7 inactivation stabilizes SOX9 protein promoting migration, metastasis and treatment resistance in medulloblastoma, one of the most common childhood brain tumors. Notably, expression of mutationally stabilized SOX9-T236/240A in medulloblastoma cells coincides with activation of pro-metastatic genes. FBW7 is frequently downregulated in all medulloblastoma subgroups and mutated specifically in SHH-driven medulloblastoma. In cases where FBW7 mRNA levels are low, SOX9 protein is significantly elevated and this phenotype is associated with metastasis at diagnosis and poor patient outcome. Finally, pharmacological inhibition of PI3K/Akt/mTOR activity destabilizes SOX9 in a GSK3/FBW7-dependent manner, rendering medulloblastoma cells sensitive to cytostatic treatment.
|
| |
|
| Overall design |
Triplicates of MB002 cells transduced with EV, SOX9-WT or SOX9-T236/240A.
|
| |
|
| Contributor(s) |
Rahmanto AS, Savov V, Swartling FJ, Sangfelt O |
| Citation(s) |
27625374 |
| Submission date |
Jul 12, 2016 |
| Last update date |
May 15, 2019 |
| Contact name |
Fredrik Johansson Swartling |
| Organization name |
Uppsala University
|
| Department |
Immunology, Genetics and Pathology
|
| Street address |
Dag Hammarskjölds väg 20
|
| City |
Uppsala |
| ZIP/Postal code |
752 37 |
| Country |
Sweden |
| |
|
| Platforms (1) |
|
| Samples (3) |
|
| Relations |
| BioProject |
PRJNA328820 |
| SRA |
SRP078364 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE84320_Expression_data_MB002_dox.tsv.gz |
367.1 Kb |
(ftp)(http) |
TSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
|
|
|
|
 |
