Mechanism of transcriptional regulation of the rat somatostatin receptor sst2 and sst5 genes.

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Somatostatin is not only an inhibitor of hormone secretion in the endocrine and exocrine glands but also a neuromodulator in the brain, effects of which are mediated by five somatostatin receptors (sst1-5). We previously reported that the sst5 and sst2 are major subtypes expressed in normal rat pituitaries and that sst2 dominates extremely over sst5 due to the decrease of sst5 mRNA expression in the pituitaries and that sst2 dominates extremely over sst5 due to the decrease of sst5 mRNA expression in the pituitaries from the rat treated with estrogen chronically. The aim of this study is to know the mechanism of transcriptional regulation of sst2 and sst5. The results were; (1) the 5ィイD11ィエD1-flanking region of the rat sst2 and sst5 genes were cloned and sequenced. Both genes contained single intron at the 5ィイD11ィエD1-untranslated region and lack the TATA and CCAAT boxes in the proximal upstream region of the transcription start sites. (2) The promoter analysis of deleted constructs of … More the 5ィイD11ィエD1-flanking region fused with a reporter gene demonstrated that the transcriptional regulatory elements in the proximal region is important for the full promoter activity of both genes. (3) Competitive gel shift assay and transient transfection assay demonstrated that both Sp1 and CRE sites were necessary for the full promoter activity of sst2 gene, and that proximal two Sp1 sites were essential for the promoter activity of the sst5 gene. The trans-acting factors of Sp1 and CRE sites were Sp2 and Sp3, and ATF-2 and c-Jun, respectively. Overexpression of the bicoid-related homeoprotein Ptx1 activated the promoter activity of the rat sst2 and sst5 genes, whereas Pit1 did not. Estrogen also increased the promoter activity of sst2 but decreased that of sst5, although no canonical ERE was observed. Estrogen effect on sst5 was partially reversed with coexpression of Pit1 in HeLa cells. The results of overexpression of c-jun suggested that c-jun at CRE site of the sst2 gene may mediate the activation of the sst2 promoter by estrogen receptor in the presence of estrogen. Less