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RAS promotes tumorigenesis through genomic instability induced by imbalanced expression of Aurora‐A and BRCA2 in midbody during cytokinesis
Author(s) -
Yang Gong,
MercadoUribe Imelda,
Multani Asha S.,
Sen Subrata,
Shih IeMing,
Wong KwongKwok,
Gershenson David M.,
Liu Jinsong
Publication year - 2013
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28032
Subject(s) - midbody , cytokinesis , carcinogenesis , genome instability , biology , cancer research , chromosome instability , oncogene , microbiology and biotechnology , genetics , cancer , gene , cell , cell cycle , dna damage , cell division , dna , chromosome
The oncogene RAS 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.