SRY GENE REGULATION AND YP LOSS IN PROSTATE CARCINOMA

描述：(改编自调查员的摘要)Y的丢失 染色体是最常见的细胞遗传学异常之一。 人类前列腺癌。然而，这一事件的生物学意义 目前还不得而知。性区Y(SRY)是一个映射到Yp11.3和Yp11.3的基因 已被证明是人类男性发育的触发基因， 老鼠。SRY蛋白含有高度保守的AT氨基酸区 与许多转录激活剂中发现的HMG盒同源。Dr。 特里科利和他的同事已经证明，这种基因是交替的 在前列腺癌中表达，60%的肿瘤中检测到转录本 检查过了。在SRY转录本缺失的40%的肿瘤中，SRY转录本不存在 由于肿瘤细胞的SRY基因含量的任何减少。目标 Tricoli博士的建议是理解Y染色体的意义 前列腺癌中的缺失与SRY表达有关，并确定 前列腺癌细胞中SRY基因调控的因素。 这些研究将使用新鲜的前列腺癌组织和 前列腺癌PC-3、DU145、LNCaP和TSU-PR1细胞株。这些研究 将包括接触制剂的间期FISH分析 以确定肿瘤中Y染色体丢失的频率和程度。这些 区域Y损失的分子分析将补充这项研究。 区域定位的Y染色体探针和从邻近组织中提纯的DNA 触摸准备部分。这些研究的结果将是 与肿瘤分期和分级相关以确定Y丢失是否相关 有更多的晚期临床疾病和患者的年龄和种族。Dr。 Tricoli和他的同事们将研究可能 潜在地调节这些细胞中SRY的表达。其中包括 睾酮、双氢睾酮和雌二醇与生长 成纤维细胞生长因子-β、PDGFa、转化生长因子-β和表皮生长因子。最后，特里科利博士将 检测SRY基因表达对前列腺癌发生的影响 在SRY缺陷细胞系PC-3中表达该基因 将该细胞注射入C.B17小鼠体内。这项实验的目的是 将利用SRY表达的PC-3细胞来鉴定表达的基因 SRY下游可能对前列腺癌的病因学有重要作用 SRY基因通路的进展和正常功能。数据 这些研究产生的结果将：1)定义Y之间的任何关系 染色体丢失与进展期肿瘤分期分级及患者年龄、种族 和无病生存，2)确定SRY基因调控和 3)确定SRY表达对肿瘤生长的生物学效应，以及 SRY下游表达的新基因的鉴定。

DESCRIPTION: (adapted from the investigator's abstract) Loss of the Y chromosome is one of the most frequent cytogenetic abnormalities observed in human prostate cancer. However, the biological significance of this event is presently unknown. Sex-region Y (SRY) is a gene which maps to Yp11.3 and has been shown to be the trigger gene for male development in humans and mice. The SRY protein contains a highly conserved AT amino acid region homologous to the HMG box found in many transcriptional activators. Dr. Tricoli and coworkers have demonstrated that this gene is alternatively expressed in prostate cancer with transcripts detected in 60% of the tumors examined. In the 40% of tumors in which SRY transcript is absent, it is not due to any reduction in the SRY gene content of the tumor cells. The goals of Dr. Tricoli's proposal are to understand the significance of Y chromosome loss in prostate cancer as it relates to SRY expression, and to identify factors responsible for regulation of the SRY gene in prostate cancer cells. These studies will be conducted using fresh prostate tumor tissue and the prostate carcinoma cell lines PC-3, DU145, LNCaP and TSU-PR1. These studies will include interphase FISH analysis of touch preparations taken from tumors to determine the frequency and extent of Y chromosomal loss. These studies will be complemented by molecular analysis for regional Y loss using regional mapped Y chromosomal probes and DNA purified from tissues adjacent to touch preparation sections. The result of these studies will be correlated with tumor stage and grade to determine if Y loss is associated with more advanced clinical disease and with patient age and race. Dr. Tricoli and coworkers will examine the effects of factors which could potentially regulate SRY expression in these cells. These include the hormones testosterone, dihydrotestosterone and estradiol and the growth factors of FGF-beta, PDGFa, TGF-beta and EGF. Finally, Dr. Tricoli will determine the effects of SRY gene expression on prostate tumorigenesis by expressing the gene in the SRY deficient cell line PC-3 followed by injection of the cells into C.B17scid mice. The goal of this experiment will be to use the SRY expression PC-3 cells to identify genes expressed downstream of SRY that may be important to the etiology of prostate tumor progression and the normal function of the SRY gene pathway. The data generated from these studies will: 1) define any relationship between Y chromosome loss and advancing tumor stage and grade and patient age, race and disease-free survival, 2) identify mechanisms of SRY gene regulation and 3) determine biological effects of SRY expression on tumorigenic growth, and the identification of novel genes which are expressed downstream of SRY.