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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    ABSTRACT: Atoh1, Hes1 and Hes5 are crucial for normal inner ear hair cell development. They regulate the expression of each other in a complex network, while they also interact with many other genes and pathways, such as Notch, FGF, SHH, WNT, BMP and RA. This paper summarized molecular pathways that involve Atoh1, Hes1, and Hes5. Some of pathways and gene regulation mechanisms discussed here were studied in other tissues, yet they might inspire studies in inner ear hair cell development. Thereby, we presented a complex regulatory network involving these three genes, which might be crucial for proliferation and differentiation of inner ear hair cells. Copyright © 2014. Published by Elsevier B.V.
    Gene 12/2014; 558(1). DOI:10.1016/j.gene.2014.12.054 · 2.08 Impact Factor
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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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    ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) is a complex disease, resulting from proliferation of differentially arrested immature T cells. The molecular mechanisms and the genes involved in the generation of T-ALL remain largely undefined. In this study, we propose a set of genes to differentiate individuals with T-ALL from the nonleukemia/healthy ones and genes that are not differential themselves but interconnected with highly differentially expressed ones. We provide new suggestions for pathways involved in the cause of T-ALL and show that network-based classification techniques produce fewer genes with more meaningful and successful results than expression-based approaches. We have identified 19 significant subnetworks, containing 102 genes. The classification/prediction accuracies of subnetworks are considerably high, as high as 98%. Subnetworks contain 6 nondifferentially expressed genes, which could potentially participate in pathogenesis of T-ALL. Although these genes are not differential, they may serve as biomarkers if their loss/gain of function contributes to generation of T-ALL via SNPs. We conclude that transcription factors, zinc-ion-binding proteins, and tyrosine kinases are the important protein families to trigger T-ALL. These potential disease-causing genes in our subnetworks may serve as biomarkers, alternative to the traditional ones used for the diagnosis of T-ALL, and help understand the pathogenesis of the disease.
    07/2013; 2013(12):210253. DOI:10.1155/2013/210253
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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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    ABSTRACT: Lung cancer is one of the leading causes of cancer death in worldwide and required for novel therapeutic strategy. Our previous research demonstrated that the crude acetone extract of Bupleurum scorzonerifolium (BS-AE) and its component isochaihulactone induce antiproliferative and apoptotic effects on the lung adenocarcinoma cell line. Structural analysis has identified isochaihulactone as a lignan, with a chiral center and two racemic forms (Z-isochaihulactone and E-isochaihulactone). In this study, Z-isochaihulactone displayed significantly higher tumor cytotoxicity than E-isochaihulactone in A549 cells. The notch signaling pathway plays a pivotal role in determination of cell fate during development, while in lung cancer, it might have oncogenic or tumor-suppressive controversial functions. We showed that Z-isochaihulactone induced morphological changes in the A549 cells, inhibited cell growth, and arrested the cell cycle at the G2/M phase. It also induced upregulation of the active form of Notch1 (notch intracellular domain, NICD), which further induced p21 and c-Myc expression in time- and dose-dependent manners. Administrations of Z-isochaihulactone in nude mice can significantly inhibit tumor growth due to enhancement of NICD expression confirmed by immunohistochemical analysis. Taken together, our results supported that Z-isochaihulactone can efficiently inhibit tumorigenicity and be a potential compound for therapy.
    Evidence-based Complementary and Alternative Medicine 09/2012; 2012:809204. DOI:10.1155/2012/809204 · 1.88 Impact Factor
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