Progesterone receptor (PR) inhibits expression of insulin-like growth factor-binding protein-1 (IGFBP-1) in human endometrial cell line HEC-1B: Characterization of the inhibitory effect of PR on the distal promoter region of the IGFBP-1 gene

Progestin has been shown to have both stimulatory and inhibitory effects on the expression of insulinlike growth factor binding protein-1 (IGFBP-1) in human endometrial cells. In this study, progestin was found to reduce levels of secreted IGFBP-1 and IGFBP-1 messenger RNA and IGFBP-1 promoter activity after stably transfecting a progesterone receptor (PR; B form) expression vector into HEC-1B cells. Deletion analysis of the IGFBP-1 promoter revealed that PR specifically inhibited promoter activity derived from a 59-bp distal BsaHI/RsaI fragment. It was concluded that PR inhibited the promoter activity through protein-protein interactions based on the facts that 1) no progesterone-responsive element was revealed by a series block mutation in the BsaHI/RsaI fragment; 2) PR bound by the antiprogesterone ZK98299 inhibited IGFBP-1 promoter activity; 3) a DNA-binding mutant of PR inhibited the IGFBP-1 promoter activity; and 4) in an in vivo competition assay, the DNA-binding domain of PR did not release the inhibitory effect of intact PR. Analysis of PR deletion mutants indicated that both transcriptional activation domains of PR (TAP-1 and TAF-2) were involved in the inhibition of IGPBP-1 expression. Thus, our data may explain the superinduction of IGFBP-1 in human endometrial cells after progestin withdrawal or progestin replacement with antiprogestin.