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RAS promotes tumorigenesis through genomic instability induced by imbalanced expression of Aurora‐A and BRCA2 in midbody during cytokinesis

The oncogene is known to induce genomic instability, leading to cancer development; the underlying mechanism, however, remains poorly understood. To better understand how RAS functions, we measured the activity of the functionally related genes Aurora‐A and BRCA2 in ovarian cancer cell lines and tum... Full description

Journal Title: International Journal of Cancer 15 July 2013, Vol.133(2), pp.275-285
Main Author: Yang, Gong
Other Authors: Mercado‐Uribe, Imelda , Multani, Asha S. , Sen, Subrata , Shih, Ie‐Ming , Wong, Kwong‐Kwok , Gershenson, David M. , Liu, Jinsong
Format: Electronic Article Electronic Article
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Subjects:
Ras
ID: ISSN: 0020-7136 ; E-ISSN: 1097-0215 ; DOI: 10.1002/ijc.28032
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title: RAS promotes tumorigenesis through genomic instability induced by imbalanced expression of Aurora‐A and BRCA2 in midbody during cytokinesis
format: Article
creator:
  • Yang, Gong
  • Mercado‐Uribe, Imelda
  • Multani, Asha S.
  • Sen, Subrata
  • Shih, Ie‐Ming
  • Wong, Kwong‐Kwok
  • Gershenson, David M.
  • Liu, Jinsong
subjects:
  • Ras
  • Aurora‐A
  • Brca2
  • Polyploid Cancer Cells
  • Cytokinesis
  • Genomic Instability
ispartof: International Journal of Cancer, 15 July 2013, Vol.133(2), pp.275-285
description: The oncogene is known to induce genomic instability, leading to cancer development; the underlying mechanism, however, remains poorly understood. To better understand how RAS functions, we measured the activity of the functionally related genes Aurora‐A and BRCA2 in ovarian cancer cell lines and tumor samples containing RAS mutations. We found that Aurora‐A and BRCA2 inversely controlled RAS‐associated genomic instability and ovarian tumorigenesis through regulation of cytokinesis and polyploidization. Overexpression of mutated RAS ablated BRCA2 expression but induced Aurora‐A accumulation at the midbody, leading to abnormal cytokinesis and ultimately chromosomal instability via polyploidy in cancer cells. RAS regulates the expression of Aurora‐A and BRCA2 through dysregulated protein expression of farnesyl protein transferase β and insulin‐like growth factor binding protein 3. Our results suggest that the imbalance in expression of Aurora‐A and BRCA2 regulates RAS‐induced genomic instability and tumorigenesis. What's new? The mechanism underlying ‐induced genomic instability, an event associated with cancer development, has remained poorly understood. Here, in an attempt to better understand the phenomenon, transformation was found to be associated with ablated expression of the tumor suppressor and accumulation of Aurora‐A during cytokinesis. The tumorigenicity of cancer cells with RAS mutation is determined by the expression ratio of BRCA2 and Aurora‐A. The regulation of Aurora‐A and BRCA‐2 was further discovered to be mediated through insulin‐like growth factor binding protein 3 and farnesyl protein transferase beta in the presence of mutated RAS. These findings suggest that BRCA2 and Aurora‐A signaling loop plays a critical role and may provide novel targets for therapeutic intervention in RAS‐mutated cancers.
language:
source:
identifier: ISSN: 0020-7136 ; E-ISSN: 1097-0215 ; DOI: 10.1002/ijc.28032
fulltext: fulltext
issn:
  • 0020-7136
  • 00207136
  • 1097-0215
  • 10970215
url: Link


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titleRAS promotes tumorigenesis through genomic instability induced by imbalanced expression of Aurora‐A and BRCA2 in midbody during cytokinesis
creatorYang, Gong ; Mercado‐Uribe, Imelda ; Multani, Asha S. ; Sen, Subrata ; Shih, Ie‐Ming ; Wong, Kwong‐Kwok ; Gershenson, David M. ; Liu, Jinsong
ispartofInternational Journal of Cancer, 15 July 2013, Vol.133(2), pp.275-285
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subjectRas ; Aurora‐A ; Brca2 ; Polyploid Cancer Cells ; Cytokinesis ; Genomic Instability
descriptionThe oncogene is known to induce genomic instability, leading to cancer development; the underlying mechanism, however, remains poorly understood. To better understand how RAS functions, we measured the activity of the functionally related genes Aurora‐A and BRCA2 in ovarian cancer cell lines and tumor samples containing RAS mutations. We found that Aurora‐A and BRCA2 inversely controlled RAS‐associated genomic instability and ovarian tumorigenesis through regulation of cytokinesis and polyploidization. Overexpression of mutated RAS ablated BRCA2 expression but induced Aurora‐A accumulation at the midbody, leading to abnormal cytokinesis and ultimately chromosomal instability via polyploidy in cancer cells. RAS regulates the expression of Aurora‐A and BRCA2 through dysregulated protein expression of farnesyl protein transferase β and insulin‐like growth factor binding protein 3. Our results suggest that the imbalance in expression of Aurora‐A and BRCA2 regulates RAS‐induced genomic instability and tumorigenesis. What's new? The mechanism underlying ‐induced genomic instability, an event associated with cancer development, has remained poorly understood. Here, in an attempt to better understand the phenomenon, transformation was found to be associated with ablated expression of the tumor suppressor and accumulation of Aurora‐A during cytokinesis. The tumorigenicity of cancer cells with RAS mutation is determined by the expression ratio of BRCA2 and Aurora‐A. The regulation of Aurora‐A and BRCA‐2 was further discovered to be mediated through insulin‐like growth factor binding protein 3 and farnesyl protein transferase beta in the presence of mutated RAS. These findings suggest that BRCA2 and Aurora‐A signaling loop plays a critical role and may provide novel targets for therapeutic intervention in RAS‐mutated cancers.
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titleRAS promotes tumorigenesis through genomic instability induced by imbalanced expression of Aurora‐A and BRCA2 in midbody during cytokinesis
descriptionThe oncogene is known to induce genomic instability, leading to cancer development; the underlying mechanism, however, remains poorly understood. To better understand how RAS functions, we measured the activity of the functionally related genes Aurora‐A and BRCA2 in ovarian cancer cell lines and tumor samples containing RAS mutations. We found that Aurora‐A and BRCA2 inversely controlled RAS‐associated genomic instability and ovarian tumorigenesis through regulation of cytokinesis and polyploidization. Overexpression of mutated RAS ablated BRCA2 expression but induced Aurora‐A accumulation at the midbody, leading to abnormal cytokinesis and ultimately chromosomal instability via polyploidy in cancer cells. RAS regulates the expression of Aurora‐A and BRCA2 through dysregulated protein expression of farnesyl protein transferase β and insulin‐like growth factor binding protein 3. Our results suggest that the imbalance in expression of Aurora‐A and BRCA2 regulates RAS‐induced genomic instability and tumorigenesis. What's new? The mechanism underlying ‐induced genomic instability, an event associated with cancer development, has remained poorly understood. Here, in an attempt to better understand the phenomenon, transformation was found to be associated with ablated expression of the tumor suppressor and accumulation of Aurora‐A during cytokinesis. The tumorigenicity of cancer cells with RAS mutation is determined by the expression ratio of BRCA2 and Aurora‐A. The regulation of Aurora‐A and BRCA‐2 was further discovered to be mediated through insulin‐like growth factor binding protein 3 and farnesyl protein transferase beta in the presence of mutated RAS. These findings suggest that BRCA2 and Aurora‐A signaling loop plays a critical role and may provide novel targets for therapeutic intervention in RAS‐mutated cancers.
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titleRAS promotes tumorigenesis through genomic instability induced by imbalanced expression of Aurora‐A and BRCA2 in midbody during cytokinesis
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abstractThe oncogene is known to induce genomic instability, leading to cancer development; the underlying mechanism, however, remains poorly understood. To better understand how RAS functions, we measured the activity of the functionally related genes Aurora‐A and BRCA2 in ovarian cancer cell lines and tumor samples containing RAS mutations. We found that Aurora‐A and BRCA2 inversely controlled RAS‐associated genomic instability and ovarian tumorigenesis through regulation of cytokinesis and polyploidization. Overexpression of mutated RAS ablated BRCA2 expression but induced Aurora‐A accumulation at the midbody, leading to abnormal cytokinesis and ultimately chromosomal instability via polyploidy in cancer cells. RAS regulates the expression of Aurora‐A and BRCA2 through dysregulated protein expression of farnesyl protein transferase β and insulin‐like growth factor binding protein 3. Our results suggest that the imbalance in expression of Aurora‐A and BRCA2 regulates RAS‐induced genomic instability and tumorigenesis. What's new? The mechanism underlying ‐induced genomic instability, an event associated with cancer development, has remained poorly understood. Here, in an attempt to better understand the phenomenon, transformation was found to be associated with ablated expression of the tumor suppressor and accumulation of Aurora‐A during cytokinesis. The tumorigenicity of cancer cells with RAS mutation is determined by the expression ratio of BRCA2 and Aurora‐A. The regulation of Aurora‐A and BRCA‐2 was further discovered to be mediated through insulin‐like growth factor binding protein 3 and farnesyl protein transferase beta in the presence of mutated RAS. These findings suggest that BRCA2 and Aurora‐A signaling loop plays a critical role and may provide novel targets for therapeutic intervention in RAS‐mutated cancers.
doi10.1002/ijc.28032
pages275-285
date2013-07-15