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. ? ?
| Melmed, Shlomo (2016) Pituitary Medicine From Discovery to Patient-Focused Outcomes. J Clin Endocrinol Metab 101:769-77 |
| Melmed, Shlomo (2015) Pituitary tumors. Endocrinol Metab Clin North Am 44:1-9 |
| Zhou, Cuiqi; Jiao, Yonghui; Wang, Renzhi et al. (2015) STAT3 upregulation in pituitary somatotroph adenomas induces growth hormone hypersecretion. J Clin Invest 125:1692-702 |
| Cuevas-Ramos, Daniel; Carmichael, John D; Cooper, Odelia et al. (2015) A structural and functional acromegaly classification. J Clin Endocrinol Metab 100:122-31 |
| Ben-Shlomo, Anat; Mirocha, James; Gwin, Stephanie M et al. (2014) Clinical factors associated with biochemical adrenal-cortisol insufficiency in hospitalized patients. Am J Med 127:754-762 |
| Donangelo, Ines; Ren, Song-Guang; Eigler, Tamar et al. (2014) Sca1? murine pituitary adenoma cells show tumor-growth advantage. Endocr Relat Cancer 21:203-16 |
| Carmichael, John D; Bonert, Vivien S; Nuño, Miriam et al. (2014) Acromegaly clinical trial methodology impact on reported biochemical efficacy rates of somatostatin receptor ligand treatments: a meta-analysis. J Clin Endocrinol Metab 99:1825-33 |
| Keeley, Patrick W; Zhou, Cuiqi; Lu, Lu et al. (2014) Pituitary tumor-transforming gene 1 regulates the patterning of retinal mosaics. Proc Natl Acad Sci U S A 111:9295-300 |
| Zhou, C; Tong, Y; Wawrowsky, K et al. (2014) PTTG acts as a STAT3 target gene for colorectal cancer cell growth and motility. Oncogene 33:851-61 |
| Eigler, Tamar; Ben-Shlomo, Anat; Zhou, Cuiqi et al. (2014) Constitutive somatostatin receptor subtype-3 signaling suppresses growth hormone synthesis. Mol Endocrinol 28:554-64 |
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