title: RAS promotes tumorigenesis through genomic instability induced by imbalanced expression of Aurora-A and BRCA2 in midbody during cytokinesis.
abstract: 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.
authors: Cancer Research Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China. yanggong@fudan.edu.cn
authors: Gong
authors: G
authors: Yang
authors: Imelda
authors: I
authors: Mercado-Uribe
authors: Asha S
authors: AS
authors: Multani
authors: Subrata
authors: S
authors: Sen
authors: Ie-Ming
authors: IeM
authors: Shih
authors: Kwong-Kwok
authors: KK
authors: Wong
authors: David M
authors: DM
authors: Gershenson
authors: Jinsong
authors: J
authors: Liu
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000378:metabolism; D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D024682:BRCA2 Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D003582:Cytogenetics; D048749:Cytokinesis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D007150:Immunohistochemistry; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D018631:ras Proteins