CYCLIN DEPENDENT KINASE INHIBITORS IN BENIGN AND MALIGNANT PROSTATIC DISEASES

良性和恶性前列腺疾病中的细胞周期蛋白依赖性激酶抑制剂

• 批准号: 6366949
• 负责人: CARLOS CORDON-CARDO
• 金额: $ 24.17万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6366949
• 关键词: androgens; benign prostate hyperplasia; cyclin dependent kinase; enzyme inhibitors; gene expression; gene mutation; genetically modified animals; hormone related neoplasm /cancer; immunocytochemistry; in situ hybridization; laboratory mouse; metastasis; methylation; neoplasm /cancer genetics; neoplastic process; nucleic acid sequence; oncoproteins; prostate neoplasms; restriction fragment length polymorphism; single strand conformation polymorphism

The objective of our research focuses on the continued characterization of mutations and altered expression patterns of cyclin-dependent kinase inhibitors (CKI) as they rate to processes of tumorigenesis and tumor progression in prostate cancer. It is our hypothesis that abnormalities of KIP and INK genes, as well as those that affect their encoded products, produce a selective advantage for prostate growth and an aggressive behavior in prostate cancer patients. The Specific Aims are outlined as follows: Aim #1: To determine the frequency and potential clinical relevance of mutations affecting the KIP genes, as well as altered patterns of expression of their encoded proteins, in benign prostatic hyperplasia (BPH) and prostate carcinoma. We have found distinct p27 anomalies in BPH and prostate tumors, supporting the postulate that BPH is not a premalignant lesion. Moreover, prostatic carcinomas displaying a p27 negative phenotype were found to be biologically more aggressive. We plan to validate these observations and to study p21 and p57 genes. Aim #2: To define the rate and possible clinical relevance of mutations arising in the INK genes, as well as altered patterns of expression of their encoded products, in BPH and prostatic carcinoma. Preliminary data reveals that altered patterns of p16 expression and methylation of he p16 promoter are frequent events in prostate cancer. We plan to extend and validate these data and to assess the relevance of alterations affecting p18 and p19. Aim #3: To further characterize the histopathology of prostatic tissue in animal models for loss of KIP or INK function, and to produce transgenic models using tissue-specific promoters. We have engineered CKI knockout mice (ie, p27 and Ink4a). p27 mull mice develop hyper-cellular prostatic glands; however,over prostate neoplasms are not observed. Transgenic mice will be generated using cyclins E or each D-type fused to the rat probasin promoter in the presence and absence of either p27 or p16. A model mimicking the human disease is expected. The goal is to translated basic and clinical research findings into clinical studies, and to collaborate with the O'Brien Centers and members of the scientific community, evaluating tumor markers of potential relevance.

我们的研究目标集中在持续表征 细胞周期蛋白依赖性激酶的突变和改变的表达模式 抑制剂（CKI），因为它们与肿瘤发生和肿瘤生长的过程有关。 前列腺癌的进展。我们的假设是 KIP和INK基因，以及那些影响其编码产物的基因， 对前列腺生长产生选择性优势， 前列腺癌患者的行为。具体目标概述如下： 如下所示： 目的#1：确定以下事件的发生频率和潜在临床相关性 影响KIP基因的突变，以及 其编码蛋白在良性前列腺增生中的表达 (BPH)和前列腺癌。我们在BPH中发现了明显的p27异常， 和前列腺肿瘤，支持BPH不是一种恶性肿瘤的假设。 癌前病变此外，前列腺癌显示p27 发现阴性表型在生物学上更具侵袭性。我们计划 以验证这些观察结果并研究p21和p57基因。 目的#2：确定突变的发生率和可能的临床相关性 出现在INK基因，以及改变的表达模式， 其编码产物在BPH和前列腺癌中的表达。初步数据 揭示了p16表达和甲基化的改变模式， 启动子是前列腺癌中的常见事件。我们计划扩大和 验证这些数据，并评估影响 P18和P19。 目的#3：进一步表征前列腺组织的组织病理学特征， 用于KIP或INK功能丧失的动物模型，并产生转基因 使用组织特异性启动子的模型。我们设计了CKI基因敲除 小鼠（即，p27和Ink 4a）。p27小鼠前列腺增生 腺体;然而，未观察到前列腺肿瘤。转基因小鼠 将使用与大鼠probasin融合的细胞周期蛋白E或每种D型产生 启动子在存在和不存在p27或p16的情况下。模型 模仿人类疾病是可以预期的。 目标是将基础和临床研究成果转化为 临床研究，并与奥布莱恩中心和成员合作 科学界，评估潜在的肿瘤标志物， 本案无关