Neoplasms are commonly characterized by abnormal gene expression. Our studies will utilize a unique murine pituitary tumor model (MGH 101A) to investigate altered gene activity. This tumor evolved in our laboratory from a thyrotropic tumor. It is unique in that it has lost completely the ability to produce the beta-subunit of TSH and now only synthesizes the alpha-subunit in a nonregulated and promiscuous fashion. Our preliminary observations suggest that these defects occur at a pretranscriptional level. The projected studies on this pituitary neoplasm will be divided into two parts. First, we will investigate the molecular basis for absent TSH-beta subunit production in MGH 101A. The production of the TSH-beta subunit is normally a highly tissue-specific function in thyrotropic tissue. Its absence could therefore be related to an abnormality in the TSH-beta gene structure or the presence of a transacting factor altering the expression of this gene. Our preliminary experiments have shown that the TSH-beta gene is present and is not grossly abnormal. We will therefore use recombinant DNA techniques and molecular biology to discover the mechanisms for the absent TSH-beta gene expression. A solution to this problem could provide insights into similar phenomena for eutopic and ectopic malignancies, as well as an understanding of those factors which regulate gene expression in eukaryotic cells. Second, we will perform studies to determine the molecular basis for the absent regulation of the alpha-subunit production in this tumor. These experiments will explore those factors of gene structure and cellular environment which are important to the regulation of gent expression. Preliminary information suggests that not only is the alpha-subunit gene present, but that it is transcribed very efficiently. Knowledge gained on the regulation of this tumor's alpha-subunit production may contribute substantive information on pathogenetic mechanisms as well as the treatment of human pituitary and non-pituitary neoplasms.

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National Cancer Institute (NCI)
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Biochemical Endocrinology Study Section (BCE)
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University of Colorado Denver
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Charles, Michael A; Saunders, Thomas L; Wood, William M et al. (2006) Pituitary-specific Gata2 knockout: effects on gonadotrope and thyrotrope function. Mol Endocrinol 20:1366-77
Christoffolete, Marcelo A; Ribeiro, Rogerio; Singru, Praful et al. (2006) Atypical expression of type 2 iodothyronine deiodinase in thyrotrophs explains the thyroxine-mediated pituitary thyrotropin feedback mechanism. Endocrinology 147:1735-43
Gordon, David F; Tucker, Elizabeth A; Tundwal, Kavita et al. (2006) MED220/thyroid receptor-associated protein 220 functions as a transcriptional coactivator with Pit-1 and GATA-2 on the thyrotropin-beta promoter in thyrotropes. Mol Endocrinol 20:1073-89
Sarapura, Virginia D; Wood, William M; Woodmansee, Whitney W et al. (2006) Pituitary tumors arising from glycoprotein hormone alpha-subunit-deficient mice contain transcription factors and receptors present in thyrotropes. Pituitary 9:11-8
Woodmansee, Whitney W; Kerr, Janice M; Tucker, Elizabeth A et al. (2006) The proliferative status of thyrotropes is dependent on modulation of specific cell cycle regulators by thyroid hormone. Endocrinology 147:272-82
Kerr, Janice M; Gordon, David F; Woodmansee, Whitney W et al. (2005) Growth arrest of thyrotropic tumors by thyroid hormone is correlated with novel changes in Wnt-10A. Mol Cell Endocrinol 238:57-67
Woodmansee, Whitney W; Mouser, Rhonda L; Gordon, David F et al. (2002) Mutational analysis of the mouse somatostatin receptor type 5 gene promoter. Endocrinology 143:2268-76
Wood, William M; Sarapura, Virginia D; Dowding, Janet M et al. (2002) Early gene expression changes preceding thyroid hormone-induced involution of a thyrotrope tumor. Endocrinology 143:347-59
Brinkmeier, M L; Stahl, J H; Gordon, D F et al. (2001) Thyroid hormone-responsive pituitary hyperplasia independent of somatostatin receptor 2. Mol Endocrinol 15:2129-36
Woodmansee, W W; Gordon, D F; Dowding, J M et al. (2000) The effect of thyroid hormone and a long-acting somatostatin analogue on TtT-97 murine thyrotropic tumors. Thyroid 10:533-41

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