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| Status |
Public on May 07, 2011 |
| Title |
The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
The NF-κB pathway is a critical regulator of the immune system and has been implicated in cellular transformation and tumorigenesis. NF-κB response is regulated by the activation state of the IκB kinase (IKK) complex and triggered by a wide spectrum of stimuli. We previously reported that NF-κB is downstream of Notch1 in T cell acute lymphoblastic leukaemia (T-ALL), however both the mechanisms involving Notch1-induced NF-κB activation and the potential importance of NF-κB in the maintenance of the disease are unknown. Here we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models of this type of leukemia. We show that it is not Notch1 itself but Hes1, a canonical Notch target, the responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by a direct transcriptional repression of the deubiquitinating enzyme CYLD, a well-characterized IKK inhibitor. Consistently, CYLD expression is significantly reduced in primary T-ALL leukemias. Finally, we demonstrate that IKK complex inhibition is a promising option for the targeted therapy of T-ALL as suppression of IKK function affected both the survival of human T-ALL cells in vitro and the maintenance of the disease in vivo.
Transcriptional consequences of NF-kB inactivation in human T-ALL1 cell line
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| Overall design |
Twenty samples were analyzed: human T-ALL, CEM, KOPT-K, DND41, HPB-ALL cells lines have been treated at 100uM for 16 hours with control peptide or IKKγ Nemo binding domain (NBD) inhibitory peptide, that specifically block the canonical NF-κB activity by disrupting the interaction of IKKγ to IKKβ and IKKα
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| Contributor(s) |
Espinosa L, Cathelin S, D’Altri T, Trimarchi T, Guiu J, Rodilla V, Inglés-Esteve J, Nomdedeu J, Bellosillo B, Besses C, Rajewsky K, Aifantis I, Bigas A |
| Citation(s) |
20832754 |
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| Submission date |
Mar 07, 2010 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Iannis Aifantis |
| E-mail(s) |
[email protected]
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| Phone |
(212) 263 5365
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| Organization name |
NYU Sch of Medicine
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| Department |
Pathology
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| Lab |
MSB 538
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| Street address |
550 First Ave
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10016 |
| Country |
USA |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (20)
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| Relations |
| BioProject |
PRJNA124923 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE20667_RAW.tar |
96.1 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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