NOVEL MITOTIC CHECKPOINT GENE

描述：（改编自研究者摘要）癌症的一个标志是 细胞周期检查点失活导致细胞失调 增殖和遗传不稳定性。其中一个检查站经常 在癌症中失活的细胞通过有丝分裂监测进展。失去这位 检查点会导致遗传物质分离过程中的错误， 有丝分裂和临床重要，因为有缺陷的有丝分裂检查点 赋予对有丝分裂应激的增加的敏感性。事实上，许多代理商 对癌症治疗有效的药物，如紫杉醇、长春新碱等， 诱导有丝分裂应激。几个人类有丝分裂检查点基因已经被 鉴定，通常作为酵母基因的同源物，但是，除了两种情况下， 这些基因在人类癌症或癌细胞中突变 线他们发现了一种新的人类有丝分裂检查点基因， 称为CHFR。在一组8种人类癌细胞系中，chfr mRNA和 蛋白在三个品系中检测不到，一个错义失活突变 在第四行中被识别。当暴露于有丝分裂应激时，细胞系 表达野生型chfr的细胞系停滞在G2期或前期，而表达野生型chfr的细胞系 丧失chfr功能的细胞经过前期，在中期停滞。 因此，与所有先前已知的有丝分裂检查点基因不同， 从中期到后期的过渡，CHFR定义了一种新的早期有丝分裂 检查站 序列分析表明chfr可能是一种泛素-蛋白质连接酶。基于 根据他们的初步结果和序列信息，他们假设 CHFR是一种有丝分裂检查点基因， 癌症，并发挥其检查点功能，作为一个 泛素蛋白连接酶他们提出了以下具体目标来测试 该假设：1）细胞系和原发性肿瘤中的Chfr突变分析。（二） 使用分子标记来识别受调控的生化过程， 直接或间接地，通过CHFR。3)确定Chfr是否具有 泛素-蛋白连接酶活性，无论其泛素-蛋白连接酶 活性是检查点功能所必需的，体内Chfr是否是 多蛋白质复合物提交。4)识别体内生理靶点 Chfr的泛素-蛋白质连接酶活性。

DESCRIPTION: (Adapted from the investigator's abstract) A hallmark of cancer is inactivation of cell cycle checkpoints leading to deregulated cell proliferation and genetic instability. One of the checkpoints frequently inactivated in cancer monitors progress through mitosis. Loss of this checkpoint leads to errors in segregation of the genetic material during mitosis and is clinically important, since a defective mitotic checkpoint confers increased sensitivity to mitotic stress. Indeed, many of the agents that are effective in cancer therapy, such as taxol, vincristine and others, induce mitotic stress. Several human mitotic checkpoint genes have been identified, often as homologs of yeast genes, but, except for two cases of human primary tumors these genes are to mutated in human cancer or cancer cell lines. They identified a novel human mitotic checkpoint gene, hereafter referred to as chfr. In a panel of eight human cancer cell lines, chfr mRNA and protein were undetectable in three lines and a missense inactivating mutation was identified in a fourth line. When exposed to mitotic stress, the cell lines that expressed wild-type chfr arrested in G2 or prophase, whereas the cell line that had lost chfr function passed through prophase and arrested in metaphase. Thus, unlike all previously known mitotic checkpoint genes, which regulate the transition from metaphase to anaphase, chfr defines a novel early mitotic checkpoint. Sequence analysis suggests that chfr may be a ubiquitin-protein ligase. Based on their preliminary results and the sequence information, they hypothesize that chfr is a mitotic checkpoint gene that is frequently mutated in human cancer and which exerts its checkpoint function by acting as a ubiquitin-protein ligase. They proposed the following specific aims to test this hypothesis: 1) Chfr mutation analysis in cell lines and primary tumors. 2) Use molecular markers to identify biochemical processes that are regulated, directly or indirectly, by chfr. 3) Establish whether Chfr has ubiquitin-protein ligase activity, whether its ubiquitin-protein ligase activity is required for checkpoint function and whether in vivo Chfr is a submit of a multi-protein complex. 4) Identify in vivo physiological target(s) of the ubiquitin-protein ligase activity of Chfr.