Cargando…
IL-4-dependent Jagged1 expression/processing is associated with survival of chronic lymphocytic leukemia cells but not with Notch activation
As previously reported, chronic lymphocytic leukemia (CLL) cells show constitutive Notch1/2 activation and express the Notchligand Jagged1. Despite increasing knowledge of the impact of Notch alterations on CLL biology and pathogenesis, the role of Jagged1 expressed in CLL cells remains undefined. I...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255763/ https://www.ncbi.nlm.nih.gov/pubmed/30478302 http://dx.doi.org/10.1038/s41419-018-1185-6 |
_version_ | 1783374011280916480 |
---|---|
author | De Falco, Filomena Del Papa, Beatrice Baldoni, Stefano Sabatini, Rita Falzetti, Franca Di Ianni, Mauro Martelli, Maria Paola Mezzasoma, Federica Pelullo, Maria Marconi, Pierfrancesco Sportoletti, Paolo Screpanti, Isabella Rosati, Emanuela |
author_facet | De Falco, Filomena Del Papa, Beatrice Baldoni, Stefano Sabatini, Rita Falzetti, Franca Di Ianni, Mauro Martelli, Maria Paola Mezzasoma, Federica Pelullo, Maria Marconi, Pierfrancesco Sportoletti, Paolo Screpanti, Isabella Rosati, Emanuela |
author_sort | De Falco, Filomena |
collection | PubMed |
description | As previously reported, chronic lymphocytic leukemia (CLL) cells show constitutive Notch1/2 activation and express the Notchligand Jagged1. Despite increasing knowledge of the impact of Notch alterations on CLL biology and pathogenesis, the role of Jagged1 expressed in CLL cells remains undefined. In other cell types, it has been shown that after Notch engagement, Jagged1 not only activates Notch in signal-receiving cell, but also undergoes proteolytic activation in signal-sending cell, triggering a signaling with biological effects. We investigated whether Jagged1 expressed in CLL cells undergoes proteolytic processing and/or is able to induce Notch activation through autocrine/paracrine loops, focusing on the effect that CLL prosurvival factor IL-4 could exert on the Notch-Jagged1 system in these cells. We found that Jagged1 was constitutively processed in CLL cells and generated an intracellular fragment that translocated into the nucleus, and an extracellular fragment released into the culture supernatant. IL-4 enhanced expression of Jagged1 and its intracellular fragments, as well as Notch1/2 activation. The IL-4-induced increase in Notch1/2 activation was independent of the concomitant upregulated Jagged1 levels. Indeed, blocking Notch-Jagged1 interactions among CLL cells with Jagged1 neutralizing antibodies did not affect the expression of the Notch target Hes1. Notably, anti-Jagged1 antibodies partially prevented the IL-4-induced increase in Jagged1 processing and cell viability, suggesting that Jagged1 processing is one of the events contributing to IL-4-induced CLL cell survival. Consistent with this, Jagged1 silencing by small interfering RNA partially counteracted the capacity of IL-4 to promote CLL cell survival. Investigating the pathways whereby IL-4 promoted Notch1/2 activation in CLL cells independent of Jagged1, we found that PI3Kδ/AKT and PKCδ were involved in upregulating Notch1 and Notch2 proteins, respectively. Overall, this study provides new insights into the Notch-ligand system in CLL cells and suggests that targeting this system may be exploited as a novel/additional therapy approach for CLL. |
format | Online Article Text |
id | pubmed-6255763 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-62557632018-11-27 IL-4-dependent Jagged1 expression/processing is associated with survival of chronic lymphocytic leukemia cells but not with Notch activation De Falco, Filomena Del Papa, Beatrice Baldoni, Stefano Sabatini, Rita Falzetti, Franca Di Ianni, Mauro Martelli, Maria Paola Mezzasoma, Federica Pelullo, Maria Marconi, Pierfrancesco Sportoletti, Paolo Screpanti, Isabella Rosati, Emanuela Cell Death Dis Article As previously reported, chronic lymphocytic leukemia (CLL) cells show constitutive Notch1/2 activation and express the Notchligand Jagged1. Despite increasing knowledge of the impact of Notch alterations on CLL biology and pathogenesis, the role of Jagged1 expressed in CLL cells remains undefined. In other cell types, it has been shown that after Notch engagement, Jagged1 not only activates Notch in signal-receiving cell, but also undergoes proteolytic activation in signal-sending cell, triggering a signaling with biological effects. We investigated whether Jagged1 expressed in CLL cells undergoes proteolytic processing and/or is able to induce Notch activation through autocrine/paracrine loops, focusing on the effect that CLL prosurvival factor IL-4 could exert on the Notch-Jagged1 system in these cells. We found that Jagged1 was constitutively processed in CLL cells and generated an intracellular fragment that translocated into the nucleus, and an extracellular fragment released into the culture supernatant. IL-4 enhanced expression of Jagged1 and its intracellular fragments, as well as Notch1/2 activation. The IL-4-induced increase in Notch1/2 activation was independent of the concomitant upregulated Jagged1 levels. Indeed, blocking Notch-Jagged1 interactions among CLL cells with Jagged1 neutralizing antibodies did not affect the expression of the Notch target Hes1. Notably, anti-Jagged1 antibodies partially prevented the IL-4-induced increase in Jagged1 processing and cell viability, suggesting that Jagged1 processing is one of the events contributing to IL-4-induced CLL cell survival. Consistent with this, Jagged1 silencing by small interfering RNA partially counteracted the capacity of IL-4 to promote CLL cell survival. Investigating the pathways whereby IL-4 promoted Notch1/2 activation in CLL cells independent of Jagged1, we found that PI3Kδ/AKT and PKCδ were involved in upregulating Notch1 and Notch2 proteins, respectively. Overall, this study provides new insights into the Notch-ligand system in CLL cells and suggests that targeting this system may be exploited as a novel/additional therapy approach for CLL. Nature Publishing Group UK 2018-11-26 /pmc/articles/PMC6255763/ /pubmed/30478302 http://dx.doi.org/10.1038/s41419-018-1185-6 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article De Falco, Filomena Del Papa, Beatrice Baldoni, Stefano Sabatini, Rita Falzetti, Franca Di Ianni, Mauro Martelli, Maria Paola Mezzasoma, Federica Pelullo, Maria Marconi, Pierfrancesco Sportoletti, Paolo Screpanti, Isabella Rosati, Emanuela IL-4-dependent Jagged1 expression/processing is associated with survival of chronic lymphocytic leukemia cells but not with Notch activation |
title | IL-4-dependent Jagged1 expression/processing is associated with survival of chronic lymphocytic leukemia cells but not with Notch activation |
title_full | IL-4-dependent Jagged1 expression/processing is associated with survival of chronic lymphocytic leukemia cells but not with Notch activation |
title_fullStr | IL-4-dependent Jagged1 expression/processing is associated with survival of chronic lymphocytic leukemia cells but not with Notch activation |
title_full_unstemmed | IL-4-dependent Jagged1 expression/processing is associated with survival of chronic lymphocytic leukemia cells but not with Notch activation |
title_short | IL-4-dependent Jagged1 expression/processing is associated with survival of chronic lymphocytic leukemia cells but not with Notch activation |
title_sort | il-4-dependent jagged1 expression/processing is associated with survival of chronic lymphocytic leukemia cells but not with notch activation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6255763/ https://www.ncbi.nlm.nih.gov/pubmed/30478302 http://dx.doi.org/10.1038/s41419-018-1185-6 |
work_keys_str_mv | AT defalcofilomena il4dependentjagged1expressionprocessingisassociatedwithsurvivalofchroniclymphocyticleukemiacellsbutnotwithnotchactivation AT delpapabeatrice il4dependentjagged1expressionprocessingisassociatedwithsurvivalofchroniclymphocyticleukemiacellsbutnotwithnotchactivation AT baldonistefano il4dependentjagged1expressionprocessingisassociatedwithsurvivalofchroniclymphocyticleukemiacellsbutnotwithnotchactivation AT sabatinirita il4dependentjagged1expressionprocessingisassociatedwithsurvivalofchroniclymphocyticleukemiacellsbutnotwithnotchactivation AT falzettifranca il4dependentjagged1expressionprocessingisassociatedwithsurvivalofchroniclymphocyticleukemiacellsbutnotwithnotchactivation AT diiannimauro il4dependentjagged1expressionprocessingisassociatedwithsurvivalofchroniclymphocyticleukemiacellsbutnotwithnotchactivation AT martellimariapaola il4dependentjagged1expressionprocessingisassociatedwithsurvivalofchroniclymphocyticleukemiacellsbutnotwithnotchactivation AT mezzasomafederica il4dependentjagged1expressionprocessingisassociatedwithsurvivalofchroniclymphocyticleukemiacellsbutnotwithnotchactivation AT pelullomaria il4dependentjagged1expressionprocessingisassociatedwithsurvivalofchroniclymphocyticleukemiacellsbutnotwithnotchactivation AT marconipierfrancesco il4dependentjagged1expressionprocessingisassociatedwithsurvivalofchroniclymphocyticleukemiacellsbutnotwithnotchactivation AT sportolettipaolo il4dependentjagged1expressionprocessingisassociatedwithsurvivalofchroniclymphocyticleukemiacellsbutnotwithnotchactivation AT screpantiisabella il4dependentjagged1expressionprocessingisassociatedwithsurvivalofchroniclymphocyticleukemiacellsbutnotwithnotchactivation AT rosatiemanuela il4dependentjagged1expressionprocessingisassociatedwithsurvivalofchroniclymphocyticleukemiacellsbutnotwithnotchactivation |