Mutation and expression analysis of human BUB1 and BUB1B in aneuploid breast cancer cell lines
Mutation and expression analysis of human BUB1 and BUB1B in aneuploid breast cancer cell lines
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DOI：
10.1016/s0304-3835(00)00340-2
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发表时间：
2000-05-01
期刊：
影响因子：
9.7
通讯作者：
Petty, EM
中科院分区：
文献类型：
--
作者：
Myrie, KA;Percy, MJ;Petty, EM
遗传不稳定是乳腺癌、结直肠癌和其他类型癌症的一个显著特征。一种以染色体不稳定为特征的类型被认为在许多表现为非整倍体的实体瘤的发病机制中起重要作用。酵母检验点基因hBUB1和hBUB1B的两个相关蛋白激酶和同源物参与了结直肠癌的发病机制。当hBUB1基因突变被导入整倍体结肠癌细胞系时，它通过破坏有丝分裂检查点而表现出显性的负面效应。在BRCA2缺乏的小鼠细胞中，Bub1突变体促进生长和细胞转化。这表明包括乳腺在内的实体肿瘤中的非整倍体可能是有丝分裂检查点基因缺陷的结果，并可能是导致肿瘤进展的染色体不稳定表型的原因。我们对19个非整倍体乳腺癌细胞株进行了突变分析。没有发现突变，但我们发现了9个序列变异，其中包括5个以前未报道的hBUB1B序列变异，其中两个影响限制位点。这些核苷酸的变化都不能预测预测的蛋白质结构会发生重大变化。Northern印迹分析表明，hBUB1和hBUB1B基因在Boast细胞中有不同程度的表达。这表明，虽然这些基因的表达调控在癌症中可能很重要，但编码序列中缺乏假定的有害突变并不支持突变的hBUB1和hBUB1B等位基因在乳腺癌的发病机制中频繁发挥作用。(C)2000爱思唯尔爱尔兰科学有限公司。保留所有权利。
Genetic instability is a hallmark feature of breast, colorectal and other types of cancers. One type characterized by chromosomal instability is thought to be important in the pathogenesis of many solid tumors displaying aneuploidy. Two related protein kinases and homologues of the yeast checkpoint genes, hBUB1 and hBUB1B, have been implicated in the pathogenesis of colorectal cancers. Mutations in hBUB1 have demonstrated a dominant negative effect by disrupting the mitotic checkpoint when transfected into euploid colon cancer cell lines. In Brca2 deficient murine cells, Bub1 mutants potentiate growth and cellular transformation. This would suggest that aneuploidy in solid tumors including breast, could be the result of defects in mitotic checkpoint genes and may be responsible for a chromosomal instability phenotype contributing to tumor progression. We conducted mutational analysis of 19 aneuploid breast cancer cell lines. No mutations were found but we identified nine sequence variations including five previously unreported sequence variants in hBUB1B, two of which affect restrictions sites. None of these nucleotide changes predict significant changes in the predicted protein structure. Expression analysis by Northern blot of boast cell lines showed variable expression of hBUB1 and hBUB1B genes. This suggest that while regulation of expression of these genes may be important in cancer, the lack of putative deleterious mutations in the coding sequence does not support a frequent role for mutant hBUB1 and hBUB1B alleles in the pathogenesis of breast cancer. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.