MECHANISMS FOR PITUITARY TUMORIGENESIS

描述(申请人提供)：垂体腺瘤是一种常见的良性肿瘤，会引起生殖功能、皮质醇产生、生长、甲状腺动态平衡和局部中心压力的影响。虽然已经确定是单克隆性的，但参与垂体细胞转化的遗传机制至今仍未解决。这项提议将继续我们的工作，以表征PTTG的特性，PTTG是一种新的垂体肿瘤衍生蛋白，现已被确定为哺乳动物Securin的指标。Securin在有丝分裂过程中通过失活分离酶活性来调节相等的姐妹染色单体分离。PTTG过表达会导致染色体不稳定和非整倍体。将PTTG和降解缺陷型PTTG突变体导入人和啮齿动物脑垂体细胞，并用活细胞成像技术研究有丝分裂和染色体非整倍体。PTTG过表达(αGSU.PTTG)和PTTG缺失(PTTG-/-)转基因小鼠模型将被用来研究PTTG在垂体细胞向增生和最终腺瘤形成的发病机制中的作用。将研究妊娠期垂体增生症、雌激素治疗和性腺切除对PTTG的需求。核磁共振成像将被用来成像转基因小鼠在体内的垂体生长。PTTG的表达对垂体细胞增殖、凋亡和转化的影响将与特定的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以及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的患有自发性垂体肿瘤的细胞周期中断的转基因小鼠进行杂交。这些研究将为染色体不稳定在包括催乳素瘤、肢端肥大症、库欣病和非分泌型α-亚单位垂体腺瘤在内的垂体肿瘤的发病机制中的作用提供机械性的见解。

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.