DIFFERENTIAL REGULATION OF PIT-1 RESPONSIVE GENES BY CBP

描述：垂体特异性转录因子的表达， Pit-1对生长激素细胞、催乳激素细胞和 促甲状腺细胞谱系及其激素产物的表达。 期间 在垂体发育过程中，Pit-1基因的激活是通过以下方式完成的： Pit-1和维甲酸对远端增强子元件（Pit-1DE）的自动调节 酸（RA）。 垂体发育完成后，Pit-1也 通过元件表达和调节GH、Prl和TSH所必需的 在这些靶基因上。 Prl基因在多激素作用下 通过雌激素和PKA依赖性信号通路通过Prl 远端增强子（Prl DE）。 与Pit-1 DE对RA的反应一样， 需要Pit-1来应对雌激素。 虽然这些因素提供了 对于不同信号通路的潜在协同激活， 这种协同作用的分子机制仍然未知， 将测试最近描述的辅激活因子CREB结合蛋白 (CBP)其功能是调节Pit-1依赖性基因表达。 在三 CBP在PKA和核激素受体（NHR）信号传导中的作用 将建立CBP，Pit-1和NHR的关键领域， 反应将被描述。 对这些信号的独特见解 途径将从研究Pit-1突变的患者获得， 合并垂体激素缺乏症（CPHD）。 CBP角色的确定 作为Pit-1作用的辅因子，将进一步理解细胞特异性的 健康和疾病中的基因调控。

DESCRIPTION: Expression of the pituitary-specific transcription factor, Pit-1, is crucial for the development of somatotroph, lactotroph and thyrotroph lineages and expression of their hormonal products. During pituitary development, activation of the Pit-1 gene is accomplished by autoregulation of a distal enhancer element (Pit-1 DE) by Pit-1 and retinoic acid (RA). After pituitary development is completed, Pit-1 is also necessary for expression and regulation of GH, Prl and TSH through elements present on these target genes. The Prl gene is under multihormonal regulation by estrogen and PKA-dependent signaling pathways through a Prl distal enhancer (Prl DE). Like the Pit-1 DE response to RA, the Prl DE requires Pit-1 for its response to estrogen. While these elements provide for potential synergistic activation by diverse signaling pathways, the molecular mechanisms for this synergism remain unknown The proposed research will test whether a recently described coactivator, CREB binding protein (CBP), functions to regulate Pit-1 dependent gene expression. In three aims, the role of CBP in PKA and nuclear hormone receptor (NHR) signaling will be established and the critical domains on CBP, Pit-1 and NHR for these responses will be characterized. Unique insight into these signaling pathways will be gained from the study of Pit-1 mutations from patients with combined pituitary hormone deficiency (CPHD). Determination of CBP's role as a cofactor for Pit-1 action will further understanding of cell-specific gene regulation in health and disease.