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RESCUE OF HIPPO CO-ACTIVATOR YAP1 TRIGGERS DNA DAMAGE-INDUCED APOPTOSIS IN HEMATOLOGICAL CANCERS
Oncogene–induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and mechanisms by which apoptosis is suppressed are largely unknown. We found p...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057660/ https://www.ncbi.nlm.nih.gov/pubmed/24813251 http://dx.doi.org/10.1038/nm.3562 |
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author | Cottini, Francesca Hideshima, Teru Xu, Chunxiao Sattler, Martin Dori, Martina Agnelli, Luca Hacken, Elisa ten Bertilaccio, Maria Teresa Antonini, Elena Neri, Antonino Ponzoni, Maurilio Marcatti, Magda Richardson, Paul G. Carrasco, Ruben Kimmelman, Alec C. Wong, Kwok-Kin Caligaris-Cappio, Federico Blandino, Giovanni Kuehl, W. Michael Anderson, Kenneth C. Tonon, Giovanni |
author_facet | Cottini, Francesca Hideshima, Teru Xu, Chunxiao Sattler, Martin Dori, Martina Agnelli, Luca Hacken, Elisa ten Bertilaccio, Maria Teresa Antonini, Elena Neri, Antonino Ponzoni, Maurilio Marcatti, Magda Richardson, Paul G. Carrasco, Ruben Kimmelman, Alec C. Wong, Kwok-Kin Caligaris-Cappio, Federico Blandino, Giovanni Kuehl, W. Michael Anderson, Kenneth C. Tonon, Giovanni |
author_sort | Cottini, Francesca |
collection | PubMed |
description | Oncogene–induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53–independent, pro-apoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway co–activator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1–induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine–threonine kinase, STK4. Importantly, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a novel synthetic–lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels. |
format | Online Article Text |
id | pubmed-4057660 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
spelling | pubmed-40576602014-12-01 RESCUE OF HIPPO CO-ACTIVATOR YAP1 TRIGGERS DNA DAMAGE-INDUCED APOPTOSIS IN HEMATOLOGICAL CANCERS Cottini, Francesca Hideshima, Teru Xu, Chunxiao Sattler, Martin Dori, Martina Agnelli, Luca Hacken, Elisa ten Bertilaccio, Maria Teresa Antonini, Elena Neri, Antonino Ponzoni, Maurilio Marcatti, Magda Richardson, Paul G. Carrasco, Ruben Kimmelman, Alec C. Wong, Kwok-Kin Caligaris-Cappio, Federico Blandino, Giovanni Kuehl, W. Michael Anderson, Kenneth C. Tonon, Giovanni Nat Med Article Oncogene–induced DNA damage elicits genomic instability in epithelial cancer cells, but apoptosis is blocked through inactivation of the tumor suppressor p53. In hematological cancers, the relevance of ongoing DNA damage and mechanisms by which apoptosis is suppressed are largely unknown. We found pervasive DNA damage in hematologic malignancies including multiple myeloma, lymphoma and leukemia, which leads to activation of a p53–independent, pro-apoptotic network centered on nuclear relocalization of ABL1 kinase. Although nuclear ABL1 triggers cell death through its interaction with the Hippo pathway co–activator YAP1 in normal cells, we show that low YAP1 levels prevent nuclear ABL1–induced apoptosis in these hematologic malignancies. YAP1 is under the control of a serine–threonine kinase, STK4. Importantly, genetic inactivation of STK4 restores YAP1 levels, triggering cell death in vitro and in vivo. Our data therefore identify a novel synthetic–lethal strategy to selectively target cancer cells presenting with endogenous DNA damage and low YAP1 levels. 2014-05-11 2014-06 /pmc/articles/PMC4057660/ /pubmed/24813251 http://dx.doi.org/10.1038/nm.3562 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Cottini, Francesca Hideshima, Teru Xu, Chunxiao Sattler, Martin Dori, Martina Agnelli, Luca Hacken, Elisa ten Bertilaccio, Maria Teresa Antonini, Elena Neri, Antonino Ponzoni, Maurilio Marcatti, Magda Richardson, Paul G. Carrasco, Ruben Kimmelman, Alec C. Wong, Kwok-Kin Caligaris-Cappio, Federico Blandino, Giovanni Kuehl, W. Michael Anderson, Kenneth C. Tonon, Giovanni RESCUE OF HIPPO CO-ACTIVATOR YAP1 TRIGGERS DNA DAMAGE-INDUCED APOPTOSIS IN HEMATOLOGICAL CANCERS |
title | RESCUE OF HIPPO CO-ACTIVATOR YAP1 TRIGGERS DNA DAMAGE-INDUCED APOPTOSIS IN HEMATOLOGICAL CANCERS |
title_full | RESCUE OF HIPPO CO-ACTIVATOR YAP1 TRIGGERS DNA DAMAGE-INDUCED APOPTOSIS IN HEMATOLOGICAL CANCERS |
title_fullStr | RESCUE OF HIPPO CO-ACTIVATOR YAP1 TRIGGERS DNA DAMAGE-INDUCED APOPTOSIS IN HEMATOLOGICAL CANCERS |
title_full_unstemmed | RESCUE OF HIPPO CO-ACTIVATOR YAP1 TRIGGERS DNA DAMAGE-INDUCED APOPTOSIS IN HEMATOLOGICAL CANCERS |
title_short | RESCUE OF HIPPO CO-ACTIVATOR YAP1 TRIGGERS DNA DAMAGE-INDUCED APOPTOSIS IN HEMATOLOGICAL CANCERS |
title_sort | rescue of hippo co-activator yap1 triggers dna damage-induced apoptosis in hematological cancers |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057660/ https://www.ncbi.nlm.nih.gov/pubmed/24813251 http://dx.doi.org/10.1038/nm.3562 |
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