MECHANISMS FOR PITUITARY TUMORIGENESIS

垂体腺瘤是一种常见的良性肿瘤， 生长、生殖功能、皮质醇产生和局部中枢神经系统 压力效应。虽然最近确定是单克隆的， 涉及垂体细胞转化的遗传机制尚不清楚。 该建议将表征PTTG的转化性质， 新的垂体瘤衍生蛋白。我们使用差异RNA显示技术， 鉴定了大鼠垂体衍生转化基因（PTTG），其编码 199 a.a.新型蛋白质现在，我们将分离和研究人类PTTG， 分配它的染色体位点。PTTG表达将在激素- 分泌（PRL，GH，ACTH）和非功能性垂体瘤，及其 丰度作为垂体腺瘤分级的函数进行评估， 侵袭素、激素活性和最终的长期临床结果。 PTTG在这些肿瘤中的细胞定位也将通过 双重免疫染色和原位技术。垂体模型 增大（妊娠和雌激素诱导的泌乳素瘤）将用于 确定PTTG在垂体细胞发病机制中的表达， 增生至腺瘤形成。PTTG体外和体内转化 性质将在双琼脂转化试验、裸 评价小鼠肿瘤发生和生长因子调节。影响 还将评估诱导型PTTG表达对细胞增殖的影响。 因此，这些研究将为发病机制提供机制性见解 泌乳素瘤、肢端肥大症、库欣病和非分泌性 垂体瘤

Pituitary adenomas are common benign neoplasms giving rise to disorders of growth, reproductive function, cortisol production and local central pressure effects. Although recently determined to be monoclonal, the genetic mechanisms involved in pituitary cell transformation are unclear. This proposal will characterize the transforming properties of PTTG, a novel pituitary tumor derived protein. We used differential RNA display to identify a rat pituitary derived transforming gene (PTTG) which encodes a 199 a.a. novel protein. Now, we will isolate and study human PTTG and assign its chromosomal locus. PTTG expression will be tested in hormone- secreting (PRL, GH, ACTH) and non-functional pituitary tumors, and its abundance assessed as a function of pituitary adenoma grading, invasinenes, hormonal activity and ultimately long-term clinical outcome. Cellular localization of PTTG will also be determined in these tumors by double immunostaining and in situ techniques. Models of pituitary enlargement (pregnancy and estrogen-induced prolactinomas) will be used to determine PTTG expression in the pathogenesis of the pituicyte to hyperplasia to adenoma formation. PTTG in vitro and in vivo transforming properties will be determined in double agar transformation assays, nude mouse tumorigenesis and growth factor regulation will be assessed. Effects of inducible PTTG expression on cell proliferation will also be assessed. These studies will thus provide mechanistic insight into the pathogenesis of prolactinomas, acromegaly, Cushing's Disease and non-secreting pituitary tumors.