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Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis

The physiological role of the mitotic checkpoint protein Bub1 is unknown. To study this role, we generated a series of mutant mice with a gradient of reduced Bub1 expression using wild-type, hypomorphic, and knockout alleles. Bub1 hypomorphic mice are viable, fertile, and overtly normal despite weak...

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Autores principales: Jeganathan, Karthik, Malureanu, Liviu, Baker, Darren J., Abraham, Susan C., van Deursen, Jan M.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2064762/
https://www.ncbi.nlm.nih.gov/pubmed/17938250
http://dx.doi.org/10.1083/jcb.200706015
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author Jeganathan, Karthik
Malureanu, Liviu
Baker, Darren J.
Abraham, Susan C.
van Deursen, Jan M.
author_facet Jeganathan, Karthik
Malureanu, Liviu
Baker, Darren J.
Abraham, Susan C.
van Deursen, Jan M.
author_sort Jeganathan, Karthik
collection PubMed
description The physiological role of the mitotic checkpoint protein Bub1 is unknown. To study this role, we generated a series of mutant mice with a gradient of reduced Bub1 expression using wild-type, hypomorphic, and knockout alleles. Bub1 hypomorphic mice are viable, fertile, and overtly normal despite weakened mitotic checkpoint activity and high percentages of aneuploid cells. Bub1 haploinsufficient mice, which have a milder reduction in Bub1 protein than Bub1 hypomorphic mice, also exhibit reduced checkpoint activity and increased aneuploidy, but to a lesser extent. Although cells from Bub1 hypomorphic and haploinsufficient mice have similar rates of chromosome missegregation, cell death after an aberrant separation decreases dramatically with declining Bub1 levels. Importantly, Bub1 hypomorphic mice are highly susceptible to spontaneous tumors, whereas Bub1 haploinsufficient mice are not. These findings demonstrate that loss of Bub1 below a critical threshold drives spontaneous tumorigenesis and suggest that in addition to ensuring proper chromosome segregation, Bub1 is important for mediating cell death when chromosomes missegregate.
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spelling pubmed-20647622008-04-22 Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis Jeganathan, Karthik Malureanu, Liviu Baker, Darren J. Abraham, Susan C. van Deursen, Jan M. J Cell Biol Research Articles The physiological role of the mitotic checkpoint protein Bub1 is unknown. To study this role, we generated a series of mutant mice with a gradient of reduced Bub1 expression using wild-type, hypomorphic, and knockout alleles. Bub1 hypomorphic mice are viable, fertile, and overtly normal despite weakened mitotic checkpoint activity and high percentages of aneuploid cells. Bub1 haploinsufficient mice, which have a milder reduction in Bub1 protein than Bub1 hypomorphic mice, also exhibit reduced checkpoint activity and increased aneuploidy, but to a lesser extent. Although cells from Bub1 hypomorphic and haploinsufficient mice have similar rates of chromosome missegregation, cell death after an aberrant separation decreases dramatically with declining Bub1 levels. Importantly, Bub1 hypomorphic mice are highly susceptible to spontaneous tumors, whereas Bub1 haploinsufficient mice are not. These findings demonstrate that loss of Bub1 below a critical threshold drives spontaneous tumorigenesis and suggest that in addition to ensuring proper chromosome segregation, Bub1 is important for mediating cell death when chromosomes missegregate. The Rockefeller University Press 2007-10-22 /pmc/articles/PMC2064762/ /pubmed/17938250 http://dx.doi.org/10.1083/jcb.200706015 Text en Copyright © 2007, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
Jeganathan, Karthik
Malureanu, Liviu
Baker, Darren J.
Abraham, Susan C.
van Deursen, Jan M.
Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis
title Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis
title_full Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis
title_fullStr Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis
title_full_unstemmed Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis
title_short Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis
title_sort bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2064762/
https://www.ncbi.nlm.nih.gov/pubmed/17938250
http://dx.doi.org/10.1083/jcb.200706015
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