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Espinosa, L. et al. The Notch/Hes1 pathway sustains NF-kappaB activation through CYLD repression in T cell leukemia. Cancer Cell 18, 268-281

Cancer Research Program, Institut Municipal d'Investigacions Mèdiques, (IMIM), Hospital del Mar, 08003 Barcelona, Spain.
Cancer cell (Impact Factor: 23.89). 09/2010; 18(3):268-81. DOI: 10.1016/j.ccr.2010.08.006
Source: PubMed

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.

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    • "This effect depends on the phosphorylation of IKBKB (IKKβ), which is conducted by TAK1. Furthermore, Hes1 directly represses expression of the deubiquitinase CYLD, a negative IKK complex regulator, which is sufficient to upregulate downstream TAK1 activity, IKK phosphorylation, NFKBIA degradation, and finally, NF-κB activity (Espinosa et al., 2010; Reiley et al., 2007). Maml1 modulates NF-κB function by two possible methods in cultured cells that regulate cell survival. "
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    • "During this time, many other genes, especially the T-cell receptor (TCR) genes, are transcribed and are in " open chromatin " configuration, meaning that they are easily accessible to DNA binding proteins , like recombinases. An unusual recombinase action may lead to translocation of chromosomes [3] [5] [6]. Generally, the translocations involve abnormal juxtaposition of powerful enhancers or promoters of TCR genes with genes on other chromosomes, such as transcription factors or oncogenes [3] [7]. "
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    • "Both the HES and HRT families function as transcriptional repressors [12]. Besides, they have other downstream targets of NICD, such as p21, c-Myc, NF-κB, and cyclin D1 [12] [14] [18] [19], and the expression of these genes via NICD also has to depend on the cell context. Valproic acid (VPA) is a branched chain fatty acid used in the treatment of patients with epilepsy and other neuropsychiatric disorders [20]. "
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