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 insulin-like 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 (TAF-1 and TAF-2) were involved in the inhibition of IGFBP-1 expression. Thus, our data may explain the superinduction of IGFBP-1 in human endometrial cells after progestin withdrawal or progestin replacement with antiprogestin.
Gao
J
J
Department of Obstetrics and Gynecology, School of Medicine, State University of New York, Stony Brook 11794, USA.
Tseng
L
L
D001483:Base Sequence; D002460:Cell Line; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D006067:Gonanes / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D009154:Mutation / Q000235:genetics; D045167:Progesterone Congeners / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics* / Q000502:physiology; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection / Q000235:genetics
D006067:Gonanes; D006727:Hormone Antagonists; D018970:Insulin-Like Growth Factor Binding Protein 1; D045167:Progesterone Congeners; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D017258:Medroxyprogesterone Acetate; C053238:onapristone