Mechanisms of tumor promotion and carcinogenesis

描述(由申请人提供)：确定允许肿瘤细胞进行不受控制的增殖的机制对于理解癌症的发生至关重要。最近的研究表明，蛋白磷酸酶和蛋白激酶一样，在细胞周期调控中发挥着重要而特定的作用；因此，这些蛋白表达或调控的变化可能会影响细胞周期进程，甚至可能允许细胞进行不受调控的增殖。我们已经克隆并鉴定了四个人的PPase，其中一个命名为PP5，特别值得进一步研究。PP5抑制糖皮质激素诱导的、P53介导的导致G1/S期生长停滞的信号级联反应。对PP5活性调节机制的研究表明，PP5的表达受17-13雌二醇和缺氧诱导因子-1(HIF-1)的影响，这两个因素都是人类乳腺癌发生发展的积极因素。此外，PP5的结构性过表达有助于细胞在氧化应激期间存活，并将MCF-7细胞从雌激素依赖的表型转变为雌激素非依赖的表型。因此，PP5活性的异常也可能有助于肿瘤的发展。这一建议旨在验证蛋白质磷酸酶在细胞周期进程中发挥重要作用的假设；因此，异常表达或其正常活性的干扰可能导致肿瘤细胞的异常增殖行为。这些研究将集中于以下特定目的：目的1.继续研究PP5在糖皮质激素受体介导的信号网络中所起的作用。目的2.确定PP5在HIF-1和雌激素介导的帮助细胞存活的信号级联反应中的作用，以及在P53、GR和HIF-1介导的信号网络之间的相互作用。目的3.通过建立PP5基因敲除小鼠和PP5-loxP转基因小鼠，研究PP5在乳腺癌发生发展中的作用，探讨PP5在乳腺癌发生发展中的作用。通过这些研究，我们希望进一步表征蛋白磷酸酶在细胞周期调控中的作用，并深入了解蛋白磷酸酶如何参与肿瘤细胞的异常增殖。

DESCRIPTION (provided by applicant): Determining the mechanisms that allow neoplastic cells to undergo uncontrolled proliferation is crucial to understanding carcinogenesis. Recent studies have made it very clear that protein phosphatases, like protein kinases, play important and specific roles in cell-cycle regulation; thus alterations in the expression or regulation of these proteins may affect cell-cycle progression and could even allow cells to undergo unregulated proliferation. We have cloned and characterized four human PPases, and one, designated PP5, is particularly attractive for further studies. PP5 acts to suppress a glucocorticoid-induced, p53- mediated signaling cascade leading to the induction of G1/S-phase growth arrest. Studies into the mechanisms regulating PP5 activity have revealed that the expression of PP5 is responsive to 17-13 estradiol and hypoxia inducible factor-1 (HIF-1), which are both positive factors in the development of human breast cancer. Furthermore, the constitutive over expression of PP5 aids cell survival during oxidative stress and converts MCF-7 cells from an estrogen-dependent into an estrogen-independent phenotype. Thus, aberrant PP5 activity may also contribute to tumor development. This proposal is designed to test the hypothesis that protein phosphatases play an important role in cell cycle progression; thus, abnormal expression or the interference of their normal activity may contribute to the aberrant proliferative behavior of neoplastic cells. These studies will focus on the following specific aims: Aim 1. Continue to characterize the roles played by PP5 in glucocorticoid receptor-mediated signaling networks. Aim 2. Determine the roles of PP5 in HIF-1- and estrogen-mediated signaling cascades that aid cell survival and in cross-talk between p53-, GR- and HIF-1-mediated signaling networks. Aim 3. Determine if PP5 expression is a positive factor in the development of human breast cancer, and characterize the physiological role for PP5 through the development of PP5-knockout and PP5-loxP transgenic mice. Through these studies we hope to further characterize the role of protein phosphatases in the regulation of cell cycle control and gain insight into the how protein phosphatases may be involved in the aberrant proliferation of neoplastic cells.