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致癌作用至关重要。最近的研究已经非常清楚，蛋白磷酸酶，如蛋白激酶，在细胞周期调控中发挥重要和特定的作用;因此，这些蛋白的表达或调节的改变可能会影响细胞周期的进展，甚至可能使细胞进行不受调节的增殖。我们已经克隆并鉴定了四种人PPase，其中一种命名为PP 5，特别适合进一步研究。PP 5的作用是抑制糖皮质激素诱导的p53介导的信号级联反应，导致G1/S期生长停滞的诱导。对PP 5活性调节机制的研究表明，PP 5的表达对17-13雌二醇和缺氧诱导因子-1（HIF-1）有反应，这两种因子在人类乳腺癌的发展中都是积极因素。此外，PP 5的组成性过表达有助于氧化应激期间的细胞存活，并将MCF-7细胞从雌激素依赖型转化为雌激素非依赖型。因此，异常的PP 5活性也可能有助于肿瘤的发展。该建议旨在检验蛋白磷酸酶在细胞周期进程中发挥重要作用的假设;因此，异常表达或干扰其正常活性可能导致肿瘤细胞的异常增殖行为。这些研究将侧重于以下具体目标：目标1。继续描述PP 5在糖皮质激素受体介导的信号网络中所起的作用。目标二。确定PP 5在HIF-1和雌激素介导的信号级联中的作用，这些信号级联有助于细胞存活，并在p53，GR和HIF-1介导的信号网络之间的串扰中发挥作用。目标3：确定PP 5表达是否是人类乳腺癌发展中的阳性因素，并通过开发PP 5敲除和PP 5-loxP转基因小鼠来表征PP 5的生理作用。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.