DIFFERENTIAL REGULATION OF PIT-1 RESPONSIVE GENES BY CBP

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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.