CDC7 kinase in normal and cancer cells: potential implications for cancer treatment

项目概要/摘要 该提案的重点是细胞分裂周期7相关蛋白（CDC 7）。本提案的总体目标是 为了测试CDC 7激酶的抑制是否可能代表治疗糖尿病的有效治疗策略， 携带突变的p53蛋白的人类癌症。在我们的研究中，我们将利用人类癌细胞系以及 小鼠癌症模型。我们的工作可能会为癌症患者带来一种新的治疗方法， 靶向p53突变的人类癌细胞。CDC 7是一种细胞周期激酶， 与调控亚基DBF 4或DRF 1相互作用。DRF 1代表在CDC 7的激活过程中， DBF 4主要在体细胞分裂过程中发挥作用。DBF 4-CDC 7激酶 在G1期结束时被激活，并磷酸化复制前复合物的组分 （pre-RC），从而触发细胞进入DNA合成期（S期）。据报道，CDC 7 从酵母菌到人类，所有生物体的细胞分裂都是必需的。有几份报告记载， 具有突变的p53的人癌细胞对CDC 7抑制特别敏感。CDC 7蛋白的消耗， 或抑制其在p53突变癌细胞中的激酶活性，显示出触发肿瘤细胞凋亡。为 基于这些原因，我们决定进一步研究CDC 7蛋白及其在正常细胞增殖中的作用， 在肿瘤发生中。其他人先前的工作已经确定，CDC 7敲除小鼠在哺乳期内死亡非常早。 妊娠，从而排除了成年生物体中的CDC 7分析。为了规避这一限制， 为了研究CDC 7在后期的功能，我们的实验室开发了一种新的小鼠品系， CDC 7蛋白。这些小鼠和它们衍生的细胞为我们提供了研究细胞分子功能的工具。 CDC7。在目标1中，我们将研究CDC 7在正常非转化细胞的细胞分裂中的分子作用。 我们的初步结果表明，存在一种新的，以前没有预料到的细胞凋亡的分子机制。 这一点，将在本书中予以探讨。在目标2中，我们将分析CDC 7在人类中的其他功能。 CDC 7可能通过其在肿瘤发生中发挥重要作用。在目标3中，我们将使用鼠标 该模型忠实地再现了p53突变型三阴性乳腺癌。利用这些小鼠，我们将测试 在肿瘤发生过程中需要CDC 7。这一提议的预期总体影响是， 我们对控制细胞分裂的机制的理解，将阐明CDC 7在肿瘤发生中的新作用， 并将测试靶向CDC 7在癌症治疗中的效用。

Project Summary/Abstract This proposal focuses on cell division cycle 7-related protein (CDC7). The overarching goal of this proposal is to test whether inhibition of CDC7 kinase might represent a powerful therapeutic strategy in treatment of human cancers carrying mutated p53 protein. In our study, we will utilize human cancer cell lines as well as a mouse cancer model. Our work may lead to a novel therapeutic approach for cancer patients, specifically targeting p53-mutated human cancer cells. CDC7 is a cell cycle kinase that is activated through a physical interaction with regulatory subunits, DBF4 or DRF1. DRF1 represents the activator of CDC7 during embryogenesis, while DBF4 functions mainly during divisions of somatic cells. The DBF4-CDC7 kinase becomes activated at the end of G1 phase and phosphorylates components of the pre-replication complexes (pre-RCs), thereby triggering entry of cells into DNA synthesis phase (S phase). CDC7 was reported to be essential for cell division in all organisms studied, from yeast to humans. Several reports documented that human cancer cells with mutated p53 are particularly sensitive to CDC7 inhibition. Depletion of CDC7 protein, or inhibition of its kinase activity in p53-mutant cancer cells was shown to trigger tumor cell apoptosis. For these reasons, we decided to further study the CDC7 protein and its role in normal cell proliferation as well as in tumorigenesis. Previous work by others has established that CDC7 knockout mice die very early during gestation, thereby precluding analyses of CDC7 in an adult organism. To circumvent this limitation, and to study CDC7 function at later stages, our laboratory developed a novel mouse strain that allows us to turn off CDC7 protein. These mice and cells derived from them offer us tools to study the molecular functions of CDC7. In Aim 1, we will study the molecular role of CDC7 in cell division of normal, non-transformed cells. Our preliminary results indicate the presence of a novel, previously unanticipated molecular mechanism of cell division, which will be examined in this Aim. In Aim 2, we will analyze additional functions of CDC7 in human cancer cells, through which CDC7 may play important roles in tumorigenesis. In Aim 3, we will utilize a mouse model that faithfully recapitulates p53-mutant triple-negative breast cancers. Using these mice, we will test the requirement for CDC7 during tumorigenesis. The expected overall impact of this proposal is that it will change our understanding of mechanisms governing cell division, will elucidate novel roles of CDC7 in tumorigenesis, and will test the utility of targeting CDC7 in cancer treatment.