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¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2002: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2001: ¥2,200,000 (Direct Cost: ¥2,200,000)
We have shown through various kind of experimental system that a stimulus that triggers the onset of functional maturation of growth hormone (GH) cells in the fetal rat pituitary gland is the glucocorticoid hormones secreted from fetal adrenal gland. The adrenal glucocorticoids act on fetal pituitary gland to induce GH and GH-releasing hormone receptor (GHRH-receptor) gene expression. Our previous study showed that the induction of GHRH-receptor is brought about by the direct interaction of ligand bound glucocorticoid receptor with the proximal promoter region of the rat GHRH-receptor gene, however, the precise molecular mechanisms responsible for the induction of GH gene transcription was not elucidated, although our previous data showed the presence of a molecule that mediates glucocorticoid action. Therefore, the identification of this molecule is of a great importance for the understanding of the mechanisms of the onset of GH production in the fetal pituitary gland. In this study,
the possible involvement of the C/EBP δ in the GH gene activation as a mediator of glucocorticoid hormones.
Rat GH promoter (approximately 1.7kbp 5' flanking to the translation initiation site) directed the reporter gene expression in GH producing clonal cell line, MtT/S. The reporter gene expression was increased up to about 3-fold by the co'transfection of C/EBP δ expression plasmid. The deletion experiment suggested that the presence of binding site(s) for C/EBP δ within SOObp flanking to ATG. The C/EBP α, a closely related molecule to δ, also stimulated the GH promoter activity to a lesser extent than that of δ . Another related molecule, C/EBP β suppressed the promoter activity The co-expression study showed that the C/EBP δ act independently from pit-1, a pituitary specific transcription factor.
These results, taken as a whole, suggest that the C/EBP δ is a mediator of glucocorticoids in the fetal pituitary gland. On the other hand, human GH promoter (l.6kb) did not respond to C/EBP δ , suggesting either that the DNA element responsible for the C/EBP δ action locates up-stream region than we tested in the human GH gene or that the molecule may not participate in the GH gene regulation in humans. Less