CHARACTERIZATION OF TSC PROTEIN HAMARTIN AND TUBERIN

TSC 蛋白错构瘤蛋白和马铃薯蛋白的表征

• 批准号: 6647745
• 负责人: VIJAYA RAMESH
• 金额: $ 17.3万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6647745
• 关键词: Drosophilidae; carcinogenesis; disease /disorder model; gene expression; gene mutation; human subject; laboratory mouse; loss of heterozygosity; neoplastic growth; neoplastic transformation; neuromuscular junction; northern blottings; patient oriented research; polymerase chain reaction; protein protein interaction; protein structure function; tuberous sclerosis; tumor suppressor proteins

DESCRIPTION (provided by applicant): Tuberous sclerosis complex is multisystem disorder characterized by the widespread development of growths known as hamartomas in many tissues and organs, particularly within the brain, eyes, skin, kidneys, heart, lungs and skeleton. The most severely affected system is the central nervous system with the occurrence in affected individuals of seizures (80-90 percent), mental retardation (50-60 percent), and autism (up to 50 percent). TSC is inherited as an autosomal dominant disorder, but approximately two-thirds of affected patients are sporadic due to new germline mutations. Genetic linkage studies have shown locus heterogeneity for the disease, with at least two TSC determining genes on chromosomes 9 and 16 which have been termed TSC1 and TSC2 respectively. The TSC1 gene encodes a novel protein, hamartin that contains a single transmembrane domain and a large cytoplasmic tail with a coiled-coil domain. The TSC2 gene encodes a novel protein tuberin that contains a region of homology to the GTPase activating protein rap1GAP. We have performed a comprehensive mutational analysis of the TSC1 and TSC2 genes and noted that TSC1 mutations are significantly underrepresented in sporadic patients. However, the occurrence of the second somatic mutation in TSC lesions, particularly brain lesions is not clear. In order to understand whether this is due to cellular pleomorphism, or if haploinsufficiency of tuberin/hamartin is enough to promote tumor genesis, we will perform genetic analysis on laser capture microdissected lesions. We have identified a novel protein associated with Myc named Pam as an interacting protein for tuberin. Mutations in both the Drosophila (hiw) and C. elegans (rpm-1) homologs of Pam show synaptic overgrowth. Our hypothesis that Pam is an essential component of the tuberin-hamartin complex, particularly in the CNS where these proteins may have a critical role in cortical neuron function will be examined. The domain of Pam that interacts with tuberin reveals 90 percent similarity with the fly homolog HIW. The possible physical and genetic interaction between the Drosophila TSC2 product Gigas and HIW will be examined. Thus the studies aimed at defining the role of tuberin-hamartin in the mammalian CNS will be further strengthened by the Drosophila model system where genetic manipulations are possible. The information obtained here will elucidate the physiological functions of these tumor suppressors, which will aid in designing better therapies.

描述（由申请人提供）：结节硬化症综合体是多系统 疾病以广泛发展的增长为特征 许多组织和器官中的Hamartomas，特别是在大脑中，眼睛， 皮肤，肾脏，心脏，肺部和骨骼。受影响最严重的系统是 中枢神经系统发生在受影响的个体中 癫痫发作（80-90％），智力低下（50-60％）和自闭症（最多可 50％）。 TSC遗传为常染色体显性疾病，但 大约三分之二的受影响患者由于新的种系而零星 突变。遗传联系研究表明基因座的异质性 疾病，至少有两个TSC确定染色体9和16上的基因 分别称为TSC1和TSC2。 TSC1基因编码小说 蛋白质，含有单个跨膜结构域和大型的Hamartin 具有盘绕螺旋域的细胞质尾巴。 TSC2基因编码小说 蛋白结核素包含与GTPase激活的同源性区域 蛋白质RAP1GAP。我们已经对 TSC1和TSC2基因，并指出TSC1突变显着 零星患者的代表性不足。但是，第二个发生 TSC病变，尤其是脑病变中的体细胞突变尚不清楚。在 为了了解这是否是由于细胞多态性的，还是 Tuberin/hamartin的单倍不足足以促进肿瘤起源，我们 将对激光捕获显微解剖病变进行遗传分析。我们有 确定了一种与MYC相关的新型蛋白质，称为PAM是一种相互作用 结核素的蛋白质。果蝇（HIW）和秀丽隐杆线虫的突变 （RPM-1）PAM的同源物显示突触过度生长。我们假设Pam是 结核素 - 哈马丁蛋白复合物的必要成分，尤其是在中枢神经系统中 这些蛋白质可能在皮质神经元功能中起关键作用的地方 被检查。与Tuberin相互作用的PAM领域显示90％ 与Fly同源性HIW相似。可能的身体和遗传 将检查果蝇TSC2产品GIGAS和HIW之间的相互作用。 因此，研究旨在定义Tuberin-Hamartin在 果蝇模型系统将进一步加强哺乳动物的CNS 遗传操作是可能的。这里获得的信息将 阐明这些肿瘤抑制剂的生理功能，这将 有助于设计更好的疗法。