NOVEL MITOTIC CHECKPOINT GENE

描述：(改编自研究人员的摘要)癌症的一个特征是 细胞周期检查点失活导致细胞失控 扩散和遗传不稳定。经常出现的检查站之一 在癌症中灭活通过有丝分裂监测进展。失去这一点 检查点导致遗传物质在 有丝分裂，临床上很重要，因为有丝分裂检查点有缺陷 增加了对有丝分裂压力的敏感性。事实上，许多特工 在癌症治疗中有效的药物，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 通常被鉴定为酵母基因的同源物，但除了两例 人类原发肿瘤这些基因在人类癌症或癌细胞中发生突变 台词。他们发现了一种新的人类有丝分裂检查点基因，此后 称为CHFR。在一个由8个人类癌细胞株组成的小组中，chfr mRNA和 在三个品系中检测不到蛋白质和一个错义失活突变 是在第四行被确认的。当暴露在有丝分裂压力下时，这些细胞系 表达野生型chfr的细胞滞留在G2期或早期，而细胞系 失去chfr功能的人，经过前期，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，有丝分裂检查点基因调节 从中期到后期，chfr定义了一个新的早期有丝分裂。 检查站。 序列分析表明，chfr可能是一种泛素蛋白连接酶。基座 根据他们的初步结果和序列信息，他们假设 该基因是一种有丝分裂检查点基因，在人类中经常发生突变。 癌症，并发挥其检查点功能，作为一个 泛素-蛋白质连接酶。他们提出了以下具体目标来测试 这一假设：1)细胞系和原发肿瘤的Chfr突变分析。2) 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是否有 泛素蛋白连接酶的活性，其泛素蛋白连接酶 检查点功能需要活动，体内CHFR是否是 提交了一个多蛋白质复合体。4)确定体内生理靶点(S) 泛素蛋白连接酶活性的变化。

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.