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Hyper-active RAS/MAPK introduces cancer-specific mitotic vulnerabilities
Aneuploidy, the incorrect number of whole chromosomes, is a common feature of tumors that contributes to their initiation and evolution. Preventing aneuploidy requires properly functioning kinetochores, which are large protein complexes assembled on centromeric DNA that link mitotic chromosomes to d...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9565228/ https://www.ncbi.nlm.nih.gov/pubmed/36191188 http://dx.doi.org/10.1073/pnas.2208255119 |
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author | Herman, Jacob A. Romain, Romario R. Hoellerbauer, Pia Shirnekhi, Hazheen K. King, David C. DeLuca, Keith F. Osborne Nishimura, Erin Paddison, Patrick J. DeLuca, Jennifer G. |
author_facet | Herman, Jacob A. Romain, Romario R. Hoellerbauer, Pia Shirnekhi, Hazheen K. King, David C. DeLuca, Keith F. Osborne Nishimura, Erin Paddison, Patrick J. DeLuca, Jennifer G. |
author_sort | Herman, Jacob A. |
collection | PubMed |
description | Aneuploidy, the incorrect number of whole chromosomes, is a common feature of tumors that contributes to their initiation and evolution. Preventing aneuploidy requires properly functioning kinetochores, which are large protein complexes assembled on centromeric DNA that link mitotic chromosomes to dynamic spindle microtubules and facilitate chromosome segregation. The kinetochore leverages at least two mechanisms to prevent aneuploidy: error correction and the spindle assembly checkpoint (SAC). BubR1, a factor involved in both processes, was identified as a cancer dependency and therapeutic target in multiple tumor types; however, it remains unclear what specific oncogenic pressures drive this enhanced dependency on BubR1 and whether it arises from BubR1’s regulation of the SAC or error-correction pathways. Here, we use a genetically controlled transformation model and glioblastoma tumor isolates to show that constitutive signaling by RAS or MAPK is necessary for cancer-specific BubR1 vulnerability. The MAPK pathway enzymatically hyperstimulates a network of kinetochore kinases that compromises chromosome segregation, rendering cells more dependent on two BubR1 activities: counteracting excessive kinetochore–microtubule turnover for error correction and maintaining the SAC. This work expands our understanding of how chromosome segregation adapts to different cellular states and reveals an oncogenic trigger of a cancer-specific defect. |
format | Online Article Text |
id | pubmed-9565228 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-95652282023-04-03 Hyper-active RAS/MAPK introduces cancer-specific mitotic vulnerabilities Herman, Jacob A. Romain, Romario R. Hoellerbauer, Pia Shirnekhi, Hazheen K. King, David C. DeLuca, Keith F. Osborne Nishimura, Erin Paddison, Patrick J. DeLuca, Jennifer G. Proc Natl Acad Sci U S A Biological Sciences Aneuploidy, the incorrect number of whole chromosomes, is a common feature of tumors that contributes to their initiation and evolution. Preventing aneuploidy requires properly functioning kinetochores, which are large protein complexes assembled on centromeric DNA that link mitotic chromosomes to dynamic spindle microtubules and facilitate chromosome segregation. The kinetochore leverages at least two mechanisms to prevent aneuploidy: error correction and the spindle assembly checkpoint (SAC). BubR1, a factor involved in both processes, was identified as a cancer dependency and therapeutic target in multiple tumor types; however, it remains unclear what specific oncogenic pressures drive this enhanced dependency on BubR1 and whether it arises from BubR1’s regulation of the SAC or error-correction pathways. Here, we use a genetically controlled transformation model and glioblastoma tumor isolates to show that constitutive signaling by RAS or MAPK is necessary for cancer-specific BubR1 vulnerability. The MAPK pathway enzymatically hyperstimulates a network of kinetochore kinases that compromises chromosome segregation, rendering cells more dependent on two BubR1 activities: counteracting excessive kinetochore–microtubule turnover for error correction and maintaining the SAC. This work expands our understanding of how chromosome segregation adapts to different cellular states and reveals an oncogenic trigger of a cancer-specific defect. National Academy of Sciences 2022-10-03 2022-10-11 /pmc/articles/PMC9565228/ /pubmed/36191188 http://dx.doi.org/10.1073/pnas.2208255119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Herman, Jacob A. Romain, Romario R. Hoellerbauer, Pia Shirnekhi, Hazheen K. King, David C. DeLuca, Keith F. Osborne Nishimura, Erin Paddison, Patrick J. DeLuca, Jennifer G. Hyper-active RAS/MAPK introduces cancer-specific mitotic vulnerabilities |
title | Hyper-active RAS/MAPK introduces cancer-specific mitotic vulnerabilities |
title_full | Hyper-active RAS/MAPK introduces cancer-specific mitotic vulnerabilities |
title_fullStr | Hyper-active RAS/MAPK introduces cancer-specific mitotic vulnerabilities |
title_full_unstemmed | Hyper-active RAS/MAPK introduces cancer-specific mitotic vulnerabilities |
title_short | Hyper-active RAS/MAPK introduces cancer-specific mitotic vulnerabilities |
title_sort | hyper-active ras/mapk introduces cancer-specific mitotic vulnerabilities |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9565228/ https://www.ncbi.nlm.nih.gov/pubmed/36191188 http://dx.doi.org/10.1073/pnas.2208255119 |
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