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| Item Type: | Article |
|---|---|
| Title: | Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed-Sternberg cells |
| Creators Name: | Schwarzer, R., Doerken, B. and Jundt, F. |
| Abstract: | A major pathogenetic mechanism in classical Hodgkin lymphoma (cHL) is constitutive activation of canonical nuclear factor-{kappa}B (NF-{kappa}B) p50/p65 signaling, controlling lymphoma cell proliferation and survival. Recently, we demonstrated that aberrant Notch1 activity is a negative regulator of the B cell program in B cell-derived Hodgkin and Reed-Sternberg (HRS) cells. Despite abundant evidence for a complex context-dependent cross talk between Notch and NF-{kappa}B signaling in hematopoietic cells, it is unknown whether these pathways interact in HRS cells. Here, we show that Notch-signaling inhibition in HRS cells by the γ-secretase inhibitor (GSI) XII results in decreased alternative p52/RelB NF-{kappa}B signaling, interfering with processing of the NF-{kappa}B2 gene product p100 into its active form p52. As a result, expression of Notch and NF-κB target genes is reduced, and survival of HRS cells is impaired. Stimulation of alternative NF-{kappa}B signaling in the Hodgkin cell line L540cy by activation of the CD30 receptor rescued GSI-mediated loss of cell viability and apoptosis induction. Our data reveal that Notch is an essential upstream regulator of alternative NF-{kappa}B signaling and indicate cross talk between both the pathways in HRS cells. Therefore, we suggest that targeting the Notch pathway is a promising therapeutic option in cHL. |
| Keywords: | Notch, NF-{kappa}B, Hodgkin Lymphoma, Hodgkin and Reed-Sternberg Cells, Animals, Mice |
| Source: | Leukemia |
| ISSN: | 0887-6924 |
| Publisher: | Nature Publishing Group |
| Volume: | 26 |
| Number: | 4 |
| Page Range: | 806-813 |
| Date: | April 2012 |
| Official Publication: | https://doi.org/10.1038/leu.2011.265 |
| PubMed: | View item in PubMed |
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