MECHANISMS FOR PITUITARY TUMORIGENESIS

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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.