EXPRESSION OF CELL CYCLE PROTEINS IN BREAST CANCER

描述：（改编自研究者摘要）细胞周期蛋白依赖性 激酶（Cdks）形成协调细胞分裂的酶家族 周期 cdk的周期性激活需要它们与 称为细胞周期蛋白的蛋白质，以及它们与抑制亚基的分离， 叫CKIS 泛素-蛋白酶体介导的蛋白水解是一种主要机制 细胞周期调节因子的蛋白质水平 对促有丝分裂和抗促有丝分裂刺激的反应。 他们以前 显示在正常二倍体细胞中CKIP27的蛋白水平主要是 通过泛素-蛋白酶体系统降解调节。 同样地， 其他G1调节蛋白（细胞周期蛋白E，细胞周期蛋白D1，E2F-1）的降解是 由ubiquitin-pathway控制 正性细胞周期过度激活 调节器（例如，细胞周期蛋白，E2F-1，Cdc25）和Ckis的失活（例如， p27、p16）在肿瘤发生中起重要作用。 这些变化不活动 可以通过突变或转录沉默发生， 相应的基因，或通过蛋白质稳定性的变化。 的确， 虽然p27基因在人类肿瘤中从未发现改变，但它们在人类肿瘤中有 最近观察到，侵袭性人类结肠直肠癌已经减少， p27的表达和增强的p27特异性蛋白水解活性。 为了确定细胞周期调节因子的异常表达是否 代表了人类乳腺癌的新型预后标志物，他们将使用 免疫组织化学和原位杂交分析表达 细胞周期调节因子（p27、细胞周期蛋白D1、细胞周期蛋白E、E2 F-1和Cdc 25 B），以及 在大约600个人类乳房的档案切片中， 癌症（具体目标1）。 这些肿瘤样本，从三个 不同的肿瘤库，具有一致的正常组织， 随访 此外，每个肿瘤库都有广泛的数据库， 载有临床病理特征及标准的资料 分子标记，使他们能够确定细胞的预后价值， 循环调节器。 他们将把研究重点放在1厘米的乳腺癌上。 大小，以及从绝经前妇女获得的肿瘤。 他们假设侵袭性肿瘤增强了p27的降解， 其他细胞周期抑制剂和细胞周期降解减少 激活剂，从而获得明显的生长优势。 来测试是否 细胞周期调节蛋白的去调节蛋白水解负责 在乳腺癌中的异常表达，他们将分析肿瘤 乳房样品中的特定降解活性丰度和 参与细胞内各种泛素结合酶（Ubcs）的水平 循环调节（具体目标2）。

DESCRIPTION: (adapted from the investigator's abstract) Cyclin-dependent kinases (Cdks) form a family of enzymes that coordinate the cell division cycle. The periodic activation of cdks requires their association with proteins called cyclins, and their dissociation from inhibitory subunits, called Ckis. Ubiquitin-proteasome-mediated proteolysis is a major mechanism by which the protein levels of cell cycle regulators are regulated in response to mitogenic and anti-mitogenic stimuli. They have previously shown that in normal diploid cells protein levels of the cki p27 are mainly regulated by degradation via the ubiquitin-proteasome system. Similarly, degradation of other G1 regulatory proteins (Cyclin E, Cyclin D1, E2F-1) is controlled by the ubiquitin-pathway. Over-activation of positive cell cycle regulators (e.g., cyclins, E2F-1, Cdc25) and inactivation of Ckis (e.g., p27, p16) play a significant role in oncogenesis. These changes inactivity can occur through mutation, or transcriptional silencing of the corresponding gene, or through changes in protein stability. Indeed, although p27 gene has never been found altered in human tumors, they have recently observed that aggressive human colorectal carcinomas have reduced expression of p27 and enhanced proteolytic activity specific for p27. To determine whether the abnormal expression of cell cycle regulators represents novel prognostic markers for human breast cancer, they will use immunohistochemistry and in situ hybridization to analyze the expression of cell cycle regulators (p27, Cyclin D1, Cyclin E, E2F-1, and Cdc25 B) and their mRNA in archival sections from approximately six hundred human breast cancers (Specific Aim 1). These tumor samples, obtained from three different tumor banks, have concordant normal tissues and a long term follow-up. Furthermore, each tumor bank has an extensive data base containing information on clinico-pathological features and standard molecular markers, allowing them to determine the prognostic value of cell cycle regulators. They will focus the study on breast carcinomas 1 cm in size, and tumors obtained from pre-menopausal women. They hypothesize that aggressive tumors have enhanced degradation of p27 and other cell cycle inhibitors and decreased degradation of cell cycle activators, thus acquiring a distinct growth advantage. To test whether deregulated proteolysis of cell cycle regulatory proteins is responsible for their abnormal expression in breast carcinomas, they will analyze tumor breast samples for the abundance of specific degradation activities and for the levels of various ubiquitin conjugating enzymes (Ubcs) involved in cell cycle regulation (Specific Aim 2).