MECHANISMS FOR PITUITARY TUMORIGENESIS

描述（由申请人提供）：垂体腺瘤是一种常见的良性肿瘤，可引起生殖功能紊乱、皮质醇产生、生长、甲状腺稳态和局部中枢压力效应。虽然确定是单克隆的，但垂体细胞转化的遗传机制尚未解决。PTTG是一种新的垂体肿瘤衍生蛋白，现已被确定为哺乳动物安全蛋白的指标，本研究将继续研究PTTG的特性。在有丝分裂过程中，Securin通过灭活分离酶活性调节姐妹染色单体的分离。过表达的PTTG导致染色体不稳定和非整倍体。人类和啮齿动物的垂体细胞将被PTTG和降解缺陷PTTG突变体转染，并通过活细胞成像研究有丝分裂和染色体非整倍体。将使用垂体驱动PTTG过表达（alphaGSU.PTTG）和PTTG缺失（PTTG-/-）转基因小鼠模型来研究PTTG在垂体细胞进展到增生并最终形成腺瘤的发病机制中的作用。研究妊娠期垂体增生、雌激素治疗和性腺切除术对PTTG的要求。MRI将用于转基因小鼠体内垂体生长成像。PTTG表达对垂体细胞增殖、凋亡和转化的影响将与特异性垂体激素基因表达一起评估。为了进一步了解垂体肿瘤的发生和PTTG与其他细胞周期调节因子的相互作用，这些模型将与其他已知发生自发性垂体肿瘤的细胞周期中断的转基因小鼠交叉受精。这些研究将为染色体不稳定性在垂体肿瘤（包括催乳素瘤、肢端肥大症、库欣病和非分泌性α -亚单位垂体腺瘤）发病机制中的作用提供机制见解。

DESCRIPTION (provided by applicant): Pituitary adenomas are common benign neoplasms giving rise to disordered reproductive function, cortisol production, growth, thyroid homeostasis and local central pressure effects. Although determined to be monoclonal, the genetic mechanisms involved in pituitary cell transformation are as yet unresolved. This proposal will continue our work to characterize the properties of PTTG, a novel pituitary tumor-derived protein which has now been identified as the index mammalian securin. Securin regulates equal sister chromatid separation by inactivating separase activity during mitosis. Overexpressed PTTG causes chromosomal instability and aneuploidy. Human and rodent pituitary cells will be transfected with PTTG and degradation-deficient PTTG mutants and mitosis and chromosomal aneuploidy studied by live cell imaging. Transgenic mouse models of pituitary-driven PTTG overexpression (alphaGSU.PTTG) and of PTTG deletion (PTTG-/-) will be used to study the role of PTTG in the pathogenesis of pituicyte progression to hyperplasia and ultimately adenoma formation. The requirement of PTTG for pituitary hyperplasia during pregnancy, estrogen treatment and gonadectomy will be studied. MRI will be used to image transgenic murine pituitary growth in vivo. Effects of PTTG expression on pituitary cell proliferation, apoptosis and transformation will be assessed together with specific pituitary hormone gene expression. To gain further insight into pituitary tumorigenesis and PTTG interaction with other cell cycle regulators, these models will be cross-fertilized with other cell-cycle-disrupted transgenic mice known to develop spontaneous pituitary tumors. These studies will provide mechanistic insight into the role of chromosomal instability in the pathogenesis of pituitary tumors including prolactinomas, acromegaly, Cushing's disease and non-secreting alpha-subunit pituitary adenomas.