The Role of Chfr In Tumorigenesis

描述（由申请方提供）：Chfr是一种新鉴定的早期有丝分裂检查点蛋白，可调节进入中期。在人类癌症中，Chfr要么发生突变，要么更频繁地下调。这些观察结果表明，Chfr可能与癌症的发展有关。为了探索Chfr在肿瘤发生中的潜在作用，我们最近产生了Chfr基因敲除小鼠。我们的初步研究表明：1）Chfr缺乏导致肿瘤发病率增加，2）Chfr是有丝分裂关键激酶Aurora-A的泛素化和降解所必需的。因此，我们假设Chfr是一种肿瘤抑制因子，它通过调节Aurora-A的能力来增强其肿瘤抑制功能。在这项研究中，我们的目标是建立一个在人类癌症的发展中Chfr下调和Aurora-A过表达之间的联系。我们还将确定Aurora是否是肿瘤发生中Chfr的关键下游效应子。最后，我们的目标是描绘的有丝分裂中的Chfr的调控，通过集中在识别的Chfr相关蛋白。这里获得的知识将使我们更好地了解Chfr的失调如何与肿瘤发生相关，并将阐明染色体不稳定性可能导致人类肿瘤发生的机制。

DESCRIPTION (provided by applicant): Chfr is a newly identified early mitotic checkpoint protein that regulates entry into metaphase. Chfr is either mutated or more frequently down-regulated in human cancers. These observations suggest that Chfr may be associated with cancer development. To explore the potential role of Chfr in tumorigenesis, we have recently generated Chfr knockout mice. Our preliminary studies have demonstrate that 1) Chfr deficiency leads to increased tumor incidence, 2) Chfr is required for ubiquitination and degradation of a key mitotic kinase Aurora-A. Thus, we hypothesize that Chfr is a tumor suppressor and it elicits its tumor suppression function through its ability to regulate Aurora-A. In this study, we aim to establish a link between Chfr downregulation and Aurora-A overexpression in the development of human cancer. We will also determine whether Aurora is the key downstream effector of Chfr in tumorigenesis. Finally, we aim to delineate the regulation of Chfr in mitosis by focusing on the identification of Chfr-associated proteins. The knowledge gained here will allow us to better understand how dysregulation of Chfr is associated with tumorigenesis and will shed light on the mechanism by which chromosomal instability could contribute to tumorigenesis in humans.