MARSHALL U COBRE: SKI AND SNO TRANSCRIPTION FACTORS IN TESTICULAR CANCER

MARSHALL U COBRE：睾丸癌中的滑雪和滑雪转录因子

• 批准号: 6973109
• 负责人: LAURA L RICHARDSON
• 金额: $ 21.75万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-23 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6973109
• 关键词: biological signal transduction; cell differentiation; cell proliferation; clinical research; gene expression; genetically modified animals; laboratory mouse; microarray technology; neoplasm /cancer genetics; neoplastic transformation; protein protein interaction; protooncogene; testis neoplasms; transcription factor; western blottings

Testicular cancer is a disease that afflicts young men in their peak reproductive years. Most testicular cancers are of germ cell origin and little is known about the molecular basis of tumorigenesis in germ cells. The proto-oncogenes Ski and Sno were first identified as transforming agents in avian fibroblasts. They are widely expressed and paradoxically have been implicated in both transformation and differentiation. They act as both transcriptional activators and repressors. Preliminary data indicate that Ski and Sno are over-expressed in human testicular tumors. Ski and Sno gene expression also was detected in mouse germ cells with the highest levels observed in mitotic spermatogonia and early meiotic leptotene/zygotene spermatocytes, which span the transition between proliferation and differentiation in the germ cell lineage. Since this is the first demonstration of Ski and Sno in germ cells, their regulation and function has not been examined in germ cells These observations lead to the central hypothesis of this proposal: that altered expression of the Ski and/or Sno genes in germ cell tumors changes the nature of transcriptional regulatory complexes containing these proteins, thereby interrupting the precisely controlled proliferation necessary for normal germ cell function. The objective of this proposal is to begin to understand the function of SKI and SNO in male germ cells through two specific aims. Aim One will determine how SKI and/or SNO are altered in testicular tumors by examining gene and protein expression patterns. SKI and SNO have been implicated in several different signaling pathways, but it is unknown how they act in germ cells. Therefore, Aim Two will address this question by focusing on the protein interactions of SKI and SNO in the vitamin A deficient mouse model, in which proliferation can be controlled by the withdrawal and restoration of vitamin A. Data from this model will be used as a basis for testing the function of SKI and SNO in germ cell tumors. The data obtained from the proposed research will advance our understanding of the molecular events controlling germ cell proliferation in normal germ cells and promoting transformation in germ cell tumors.

睾丸癌是一种疾病，使年轻人在峰值生殖年中受苦。大多数睾丸癌是生殖细胞起源的，对生殖细胞中肿瘤发生的分子基础知之甚少。首先将原始基因滑雪素和SNO鉴定为鸟类成纤维细胞中的转化剂。它们被广泛表达，并且自相矛盾的是与转化和分化有关。它们既充当转录激活器和阻遏物。初步数据表明滑雪和SNO过表达 在人类睾丸肿瘤中。在小鼠生殖细胞中也检测到滑雪和SNO基因表达 在有丝分裂精子中观察到的最高水平和早期减数分裂瘦素/Zygotene 精子细胞跨越生殖细胞谱系中增殖与分化之间的过渡。 Since this is the first demonstration of Ski and Sno in germ cells, their regulation and function has not been examined in germ cells These observations lead to the central hypothesis of this proposal: that altered expression of the Ski and/or Sno genes in germ cell tumors changes the nature of transcriptional regulatory complexes containing these proteins, thereby interrupting the precisely controlled proliferation necessary for normal germ cell function.该提案的目的是通过两个特定目标开始了解男性生殖细胞中滑雪和SNO的功能。 AIM ONE将通过检查基因和蛋白质表达模式来确定在睾丸肿瘤中如何改变SKI和/或SNO。滑雪和SNO一直 与几种不同的信号通路有关，但尚不清楚它们在生殖细胞中的作用。因此，目标两个将通过关注维生素A中的SKI和SNO的蛋白质相互作用来解决这个问题，在该模型中，可以通过戒断和恢复维生素A的蛋白质模型来控制增殖。该模型的数据将用作测试生殖细胞肿瘤中SKI和SNO功能的基础。从拟议的研究中获得的数据将促进我们对控制正常生殖细胞中生殖细胞增殖的分子事件的理解，并促进生殖细胞肿瘤的转化。