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| Status |
Public on Aug 11, 2019 |
| Title |
CDK5-dependent phosphorylation and nuclear translocation of TRIM59 promotes macroH2A1 ubiquitination and tumorigenicity |
| Organism |
Homo sapiens |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
Despite the development of adjuvant therapies, glioblastoma (GBM) patients remain incurable and justify the urgent need of new therapies. CDK5 functions a critical role in GBM and is a potential target for GBM. However, the mechanism by which CDK5 promotes GBM tumorigenicity remains largely unknown. Here we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis-trans isomerization of TRIM59, leading to TRIM59 binding to importin a5 and nuclear translocation. Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity. These findings are confirmed by inhibition of CDK5-activated TRIM59 activity that results in suppression of intracranial tumor growth. Correlative expressions of the components of this pathway are clinically prognostic. Our findings suggest targeting CDK5/TRIM59 signaling axis as a putative strategy for treating GBM.
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| Overall design |
Examing of erlotinib and roscovitine on EGFRvIII-mediated macroH2A1 binding in genome wide.
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| Contributor(s) |
Feng H |
| Citation(s) |
31488827 |
| |
| Submission date |
May 09, 2019 |
| Last update date |
Sep 18, 2019 |
| Contact name |
Haizhong Feng |
| E-mail(s) |
[email protected]
|
| Phone |
862168383921
|
| Organization name |
Shanghai Jiao Tong University
|
| Department |
Ren Ji Hospital
|
| Street address |
Pujian Road 160
|
| City |
Shanghai |
| State/province |
Shanghai |
| ZIP/Postal code |
200127 |
| Country |
China |
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| Platforms (1) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA542104 |
| SRA |
SRP197304 |
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