Thyrotropin (TSH) is the pituitary glycoprotein hormone which controls the growth and function of the thyroid gland. It is produced solely by thyrotrope cells, one of five terminally differentiated pituitary cell types. The TSH molecule is composed two non-identical glycosylated subunits, alpha and TSHbeta, which are con-covalently associated. These two subunits arise independently from separate genes located on different chromosomes. The alpha-subunit is expressed not only in TSH cells but also in pituitary gonadotropes and placental cells. In contrast, TSHbeta gene expression is restricted only to thyrotropes. The studies proposed in this grant are a direct extension of our important previous contributions in which the murine TSHbeta gene was identified and sequenced, its promoter region characterized, the important functional cis-acting DNA elements determine, and important transcription factors bindings to these regions identified. Two of these transcription factors are Pit-1 and GATA-2 which interact in a unique complex on the TSHbeta promoter. Our propose studies are designed to precisely define the molecular basis for the observed synergistic interaction of Pit-1 and GATA-2. We will first map the respective sites on Pit-1 and GATA-2 that are responsible for their interaction, their DNA binding, and their ability to functionally synergize. We will precisely define the spatial and orientation requirements of their binding sites on the TSHbeta promoter. To establish the physiological in vivo role of the Pit-1/GATA-2 interaction, we will develop unique cell culture and transgenic models of targeted aberrant GATA-2 function and determine its effect on endogenous TSHbeta gene expression. These projects will utilize the most modern techniques of molecular and cell biology incorporated into cell culture and transgenic technology. These studies will provide new fundamental knowledge on the structural interactions between different classes of transcription factors and the impact of these interactions on normal physiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK036843-14
Application #
6124835
Study Section
Endocrinology Study Section (END)
Program Officer
Linder, Barbara
Project Start
1985-09-01
Project End
2002-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
14
Fiscal Year
2000
Total Cost
$291,010
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
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
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
McDermott, Michael T; Haugen, Bryan R; Black, Jennifer N et al. (2002) Congenital isolated central hypothyroidism caused by a ""hot spot"" mutation in the thyrotropin-beta gene. Thyroid 12:1141-6
Gordon, David F; Woodmansee, Whitney W; Black, Jennifer N et al. (2002) Domains of Pit-1 required for transcriptional synergy with GATA-2 on the TSH beta gene. Mol Cell Endocrinol 196:53-66
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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