Role of the transcription factor CREB in the regulation of cell proliferation in estrogen-responsive cells

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1 We generated Ad-TRE/MCREB.Tag, an adenovirus vector expressing the dominant negative CREB mutant MCREB. We verified morphologically and functionally the expression of MCREB protein.2 Infection with Ad-TRE/bgal as a negative control did not change forskolin-induced proliferation of lactotrophs whereas Ad-TRE/MCREB.Tag infection completely blocked forskolin-induced proliferation.3 Infection with Ad-TRE/MCREB.Tag partially suppressed stimulation of lactotroph proliferation by insulin-like growth factor-1 (IGF-1), a mitogen whose action is mediated by a signaling pathway distinct from the cyclic AMP/protein kinase A pathway.4 Treatment with forskolin or estradiol alone increased prolactin promoter activity and their combination further increased the promoter activity. Infection with Ad-TRE/bgal did not change basal or forskolin-induced levels of prolactin promoter activity whereas Ad-TRE/MCREB.Tag infection partially suppressed the basal and forskolin-induced levels.5 Intracellular cyclic AMP levels were markedly increased by forskolin treatment but not by IGF-1 treatment. Forskolin treatment markedly increased the proportion of phosphorylated CREB-immunoreactive lactotrophs at 20 min and up to 9 h whereas IGF-1 treatment modestly increased it only at 20 min and 1 h.