MECHANISMS FOR PITUITARY TUMORIGENESIS

垂体肿瘤发生机制

• 批准号: 7023096
• 负责人: SHLOMO MELMED
• 金额: $ 27.42万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-15 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7023096
• 关键词: aneuploidy; carcinogenesis; cell cycle; clinical research; estrogens; genetically modified animals; human tissue; laboratory mouse; magnetic resonance imaging; neoplasm /cancer genetics; neoplastic growth; neoplastic transformation; oncoproteins; ovariectomy; pituitary neoplasms; pregnancy; preneoplastic state; tissue /cell culture

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.

描述（由申请方提供）：垂体腺瘤是一种常见的良性肿瘤，可引起生殖功能、皮质醇产生、生长、甲状腺稳态和局部中枢压力效应紊乱。虽然确定是单克隆的，但垂体细胞转化中涉及的遗传机制尚未解决。该建议将继续我们的工作，以表征PTTG，一种新的垂体肿瘤衍生蛋白，现已被确定为指数哺乳动物securin的属性。Securin通过在有丝分裂过程中抑制分离酶活性来调节姐妹染色单体的相等分离。过度表达PTTG导致染色体不稳定和非整倍体。将用PTTG和降解缺陷型PTTG突变体转染人和啮齿动物垂体细胞，并通过活细胞成像研究有丝分裂和染色体非整倍性。垂体驱动的PTTG过表达（α GSU·PTTG）和PTTG缺失（PTTG-/-）的转基因小鼠模型将用于研究PTTG在垂体细胞进展为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、雌激素治疗和性腺切除术对PTTG的需求。将使用MRI对转基因小鼠垂体的体内生长进行成像。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。为了进一步深入了解垂体肿瘤发生和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会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。这些研究将为深入了解染色体不稳定性在垂体瘤（包括泌乳素瘤、肢端肥大症、库欣病和非分泌型α亚单位垂体腺瘤）发病机制中的作用提供机制。