The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia Journal Article
| Authors: | Espinosa, L.; Cathelin, S.; D'Altri, T.; Trimarchi, T.; Statnikov, A.; Guiu, J.; Rodilla, V.; Inglés-Esteve, J.; Nomdedeu, J.; Bellosillo, B.; Besses, C.; Abdel-Wahab, O.; Kucine, N.; Sun, S. C.; Song, G.; Mullighan, C. C.; Levine, R. L.; Rajewsky, K.; Aifantis, I.; Bigas, A. |
| Article Title: | The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemia |
| Abstract: | It was previously shown that the NF-κB pathway is downstream of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL). Here, we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models. We demonstrate that Hes1, a canonical Notch target and transcriptional repressor, is responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by repressing the deubiquitinase CYLD, a negative IKK complex regulator. CYLD expression was found to be significantly suppressed in primary T-ALL. Finally, we demonstrate that IKK inhibition is a promising option for the targeted therapy of T-ALL as specific suppression of IKK expression and function affected both the survival of human T-ALL cells and the maintenance of the disease in vivo. © 2010 Elsevier Inc. |
| Keywords: | signal transduction; protein expression; unclassified drug; nonhuman; protein function; mouse; animals; mice; mice, knockout; cell survival; apoptosis; protein degradation; animal experiment; basic helix-loop-helix transcription factors; notch receptor; immunoglobulin enhancer binding protein; transcription factor hes 1; cell differentiation; homeodomain proteins; transcription factor rela; in vitro study; mice, inbred balb c; mice, inbred c57bl; animalia; nf-kappa b; receptors, notch; cell growth processes; tumor suppressor proteins; t cell leukemia; genes, tumor suppressor; i kappa b; protein cyld; synaptotagmin i; leukemia, t-cell |
| Journal Title: | Cancer Cell |
| Volume: | 18 |
| Issue: | 3 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2010-09-14 |
| Start Page: | 268 |
| End Page: | 281 |
| Language: | English |
| DOI: | 10.1016/j.ccr.2010.08.006 |
| PUBMED: | 20832754 |
| PROVIDER: | scopus |
| PMCID: | PMC2963042 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 5" - "Export Date: 20 April 2011" - "CODEN: CCAEC" - "Source: Scopus" |
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