Erson Ayse E, Petty Elizabeth M
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109-0638, USA.
Mol Carcinog. 2004 Jan;39(1):26-33. doi: 10.1002/mc.10161.
Cell division is a highly regulated process. Checkpoints can halt cell-cycle progression due to adverse conditions such as misalignment of chromosomes to prevent missegregation. The search for new regulators of the cell cycle revealed the mitotic checkpoint gene CHFR (checkpoint with forkhead-associated and ring finger). CHFR coordinates an early mitotic phase by delaying chromosome condensation in response to a mitotic stress. Because aneuploidy and chromosome instability are common in malignant breast tumors, we screened 24 breast cancer cell lines for CHFR expression and demonstrated that 50% (12 of 24) of breast cancer cell lines had low CHFR levels. Expression of CHFR was reactivated with the demethylating agent 5-aza-2'-deoxycytidine (5-aza-dC) in two low-CHFR-expressing cell lines. Eleven of these 12 (92%) low-CHFR-expressing cell lines had an unusually high number of condensed chromosomes and high mitotic indices in response to nocodazole treatment. Transfection of CHFR in one of these cancer cell lines lowered the mitotic index after nocodazole treatment. In conclusion, our data suggested that low CHFR expression associated with high mitotic indices in response to nocodazole treatment were common in the breast cancer cell lines studied. Additional flow cytometry studies and analysis of a protein that interacts with CHFR in vitro, polo-like kinase 1 (PLK1), suggests that this CHFR-associated early G(2)/M checkpoint is complex, involving additional, as yet unidentified, proteins. Further analysis of CHFR in breast cancer cells will be important for understanding the complex mechanisms leading to aneuploidy and chromosomal instability observed in breast cancer.
细胞分裂是一个受到高度调控的过程。检查点可因诸如染色体排列错误等不利条件而使细胞周期进程停止，以防止错误分离。对细胞周期新调控因子的研究发现了有丝分裂检查点基因CHFR（含叉头相关结构域和环指结构的检查点）。CHFR通过响应有丝分裂应激延迟染色体凝聚来协调有丝分裂早期阶段。由于非整倍体和染色体不稳定性在恶性乳腺肿瘤中很常见，我们对24种乳腺癌细胞系进行了CHFR表达筛查，结果显示50%（24个中的12个）的乳腺癌细胞系CHFR水平较低。在两个CHFR低表达的细胞系中，用去甲基化剂5-氮杂-2'-脱氧胞苷（5-aza-dC）使CHFR表达重新激活。这12个CHFR低表达细胞系中有11个（92%）在诺考达唑处理后出现异常大量的凝聚染色体和高有丝分裂指数。在其中一个癌细胞系中转染CHFR可降低诺考达唑处理后的有丝分裂指数。总之，我们的数据表明，在研究的乳腺癌细胞系中，低CHFR表达与诺考达唑处理后的高有丝分裂指数相关是常见现象。额外的流式细胞术研究以及对一种在体外与CHFR相互作用的蛋白——polo样激酶1（PLK1）的分析表明，这种与CHFR相关的早期G(2)/M检查点很复杂，涉及其他尚未确定的蛋白。对乳腺癌细胞中CHFR进行进一步分析对于理解导致乳腺癌中观察到的非整倍体和染色体不稳定性的复杂机制将非常重要。
