CELL CYCLE REGULATORS AS TUMOR MARKERS IN BLADDER CANCER

产品说明： （申请人的描述）我们的主要目标 该提案侧重于突变的持续表征， 细胞周期表达模式改变 监管机构，因为他们 涉及 肿瘤发生和肿瘤进展的过程 膀胱癌 我们假设分子异常 TP 53和RB基因，以及那些直接或间接 影响他们的编码产品，产生选择性优势， 膀胱癌的肿瘤生长和侵袭行为 患者 这得到了以下事实的支持，即TP 53突变和 p53和pRB的表达改变是膀胱癌中常见的事件， 肿瘤，并与不良的临床结果和减少 患者生存率。 最近，9 p2 l的缺失，影响p16和p15， 已记录发生在膀胱肿瘤中， 表面损伤 此外，某些细胞周期蛋白和细胞周期蛋白- 依赖性激酶已被证明成为激活的癌基因 in a subset子集of cancers癌症. 识别这些改变可能 从而揭示了它们作为肿瘤标志物的重要临床价值， 早期发现和监测膀胱癌患者 癌症，以及预测肿瘤行为。 我们的目标 该项目旨在将基础研究成果转化为临床研究， 并与网络实验室和NCI合作 推荐的肿瘤标志物评价中的代表 协调委员会。 具体目标概述如下： 目的#1：TP 53和RB的分子和功能分析 浅表性和浸润性膀胱癌。 我们计划将来 验证了我们实验室和其他小组先前的报告， 显示TP 53和RB的预后价值。 我们还将研究- 流事件的途径，包括mdm 2和E2 F蛋白。 此外，还将进行p53和pRB的功能研究， 将沉默突变与那些导致 恶性表型 目的#2：细胞周期蛋白依赖性激酶抑制剂（CKI）的表征 膀胱癌的基因突变 由于这种隐性的性质， 新的负调节剂家族，有人认为， 作为抑制基因发挥作用。 来自我们集团和其他 共同研究者揭示，某些CKI基因（主要是p16和p15） 在膀胱肿瘤中发生了突变 我们建议确定他们是否 失活是膀胱肿瘤中的早期和常见事件。 此外，我们将测试野生型基因的重新引入是否可以 逆转膀胱癌细胞的致瘤表型。 针对性 这些基因的破坏将 进一步披露其在 发育和肿瘤发生。 目的#3：细胞周期蛋白和细胞周期蛋白的免疫表型和分子研究- 膀胱癌中的依赖性激酶。 我们已经组装了一口井 针对特异性细胞周期蛋白和Cdk的表征的探针组和计划 为了确定是否检测到异常表达模式， 的临床病理后果，这表明，他们的 鉴定具有预后价值。

DESCRIPTION: (Applicant's Description) The main objective of our proposal focuses on the continued characterization of mutations and altered patterns of expression of cell cycle regulators as they relate to processes of tumorigenesis and tumor progression in bladder cancer. It is our hypothesis that molecular abnormalities of TP53 and RB genes, as well as those that directly or indirectly affect their encoded products, produce a selective advantage for tumor growth and an aggressive behavior in bladder cancer patients. This is supported by the facts that TP53 mutations and altered expression of p53 and pRB are frequent events in bladder tumors and are associated with poor clinical outcome and reduced patient survival. Recently, deletions at 9p2l, affecting pl6 and pl5, have been documented to occur in bladder tumors and were associated with superficial lesions. In addition, certain cyclins and cyclin- dependent kinases have been shown to become activated oncogenes in a subset of cancers. Identification of these alterations may in turn reveal their important clinical value as tumor markers for the early detection and monitoring of patients affected with bladder cancer, as well as in predicting tumor behavior. The goals of our program are to translate basic research findings into clinical studies, and to collaborate with the Network laboratories and NCI representatives in the evaluation of tumor markers recommended by the Coordinating Committee. The Specific Aims are outlined as follows: Aim #1: Molecular and Functional Analyses of TP53 and RB in Superficial and Invasive Bladder Cancer. We plan to prospectively validate previous reports from our laboratory and other groups that showed the prognostic value of TP53 and RB. We will also study down- stream events of their pathways, including mdm2 and E2F proteins. Furthermore, functional studies of p53 and pRB will be conducted to distinguish silent mutations from those contributing to the malignant phenotype. Aim #2: Characterization of Cyclin-Dependent Kinase Inhibitory (CKI) Gene Mutations in Bladder Cancer. Due to the recessive nature of this new family of negative regulators, it has been suggested that they function as suppressor genes. Reports from our group and other coinvestigators revealed that certain CKI genes (mainly pl6 and pl5) are mutated in bladder tumors. We propose to determine if their inactivation is an early and frequent event in bladder tumors. Furthermore, we will test if reintroduction of wild type genes can revert the tumorigenic phenotype of bladder cancer cells. Targeted disruption of these genes will further disclose their role in development and tumorigenesis. Aim #3: Immunophenotypic and Molecular Studies of Cyclins and Cyclin- Dependent Kinases in Bladder Cancer. We have assembled a well characterized panel of probes to specific cyclins and Cdks and plan to determine if detection of abnormal patterns of expression are of clinicopathological consequences, suggesting that their identification is of prognostic value.