MECHANISMS FOR PITUITARY TUMORIGENESIS

垂体肿瘤发生机制

• 批准号: 7173718
• 负责人: SHLOMO MELMED
• 金额: $ 26.63万
• 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/7173718
• 关键词: Acromegaly; Aneuploidy; Apoptosis; Apoptotic; Benign; Breeding; Cell Cycle; Cell Proliferation; Cells; Chemosensitization; Chromosomal Instability; Development; Disease; Estrogens; Exhibits; Gene Expression; Genetic; Growth; Homeostasis; Hormones; Human; Hydrocortisone; Hyperplasia; Image; Knockout Mice; Life; Magnetic Resonance Imaging; Mitosis; Mitotic Checkpoint; Modeling; Mus; Mutant Strains Mice; Natural History; Neoplasms; Organ; PTTG1 gene; Pathogenesis; Pituitary Gland; Pituitary Gland Adenoma; Pituitary Hormones; Pituitary Neoplasms; Pituitary-dependent Cushing' s disease; Pregnancy; Production; Prolactinoma; Property; Protein Overexpression; Proteins; Rodent; Role; Sister Chromatid; Solid Neoplasm; Testing; Thyroid Gland; Tissues; Transgenes; Transgenic Mice; Transgenic Organisms; Tumor Promotion; Tumor-Derived; Work; adenoma; cell transformation; cellular imaging; fetal; human PTTG1 protein; in vivo; indexing; insight; mouse model; mutant; novel; p27 Cell Cycle Protein; p27 Enzyme Inhibitor; pressure; reproductive function; self-renewal; separase; tumor initiation; tumorigenesis

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（由申请人提供）：垂体腺瘤是常见的良性肿瘤，会导致生殖功能、皮质醇产生、生长、甲状腺稳态和局部中枢压力影响紊乱。尽管确定为单克隆，但参与垂体细胞转化的遗传机制尚未解决。该提案将继续我们的工作，以表征 PTTG 的特性，PTTG 是一种新型垂体肿瘤衍生蛋白，现已被确定为哺乳动物 securin 的指标。 Securin 通过在有丝分裂过程中灭活分离酶活性来调节姐妹染色单体的平等分离。过度表达 PTTG 会导致染色体不稳定和非整倍性。人类和啮齿动物的垂体细胞将被 PTTG 和降解缺陷的 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性。垂体驱动的 PTTG 过表达 (alphaGSU.PTTG) 和 PTTG 缺失 (PTTG-/-) 转基因小鼠模型将用于研究 PTTG 在垂体细胞进展为增生并最终形成腺瘤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中PTTG的需要。 MRI 将用于对转基因小鼠垂体体内生长进行成像。 PTTG表达对垂体细胞增殖、凋亡和转化的影响将与特定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，这些模型将与已知会发生自发性垂体肿瘤的其他细胞周期破坏的转基因小鼠进行交叉受精。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α亚基垂体腺瘤）发病机制中的作用提供机制见解。