DIFFERENTIAL REGULATION OF PIT-1 RESPONSIVE GENES BY CBP

描述：脑垂体特异性转录因子的表达， PIT-1对生长激素、乳酸菌和乳酸菌的发育至关重要。 促甲状腺激素谱系及其激素产物的表达。在.期间 垂体发育过程中，Pit-1基因的激活是通过 Pit-1和维甲酸对远端增强子元件(Pit-1 DE)的自动调节 酸(RA)。在垂体发育完成后，Pit-1也 生长激素、催乳素和促甲状腺激素的表达和调控 存在于这些靶基因上。催乳素基因处于多激素状态 雌激素和PKA依赖的信号通路通过催乳素调节 远端增强子(PRL-DE)。就像Pit-1 DE对RA的反应一样，PRL DE 需要Pit-1对雌激素的反应。虽然这些元素提供了 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尚不清楚，建议进行的研究 将测试最近描述的辅活化子CREB结合蛋白 (CBP)，功能是调节依赖Pit-1的基因表达。在三年内 AIMS、CBP在PKA和核激素受体(NHR)信号转导中的作用 将建立并在CBP、Pit-1和NHR上为这些 我们将对这些反应进行描述。对这些信号的独特见解 通路将从患者的Pit-1突变研究中获得 合并垂体激素缺乏症(CPHD)。CBP的角色定位 作为Pit-1作用的辅助因子将进一步了解细胞特异性 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.