Stuart Milligan | Search PubMed

PubMed2003

Identification of RIP140 as a nuclear receptor cofactor with a role in female reproduction.

Nuclear receptors function as ligand-dependent transcription factors by recruiting cofactors that remodel chromatin and recruit the transcription machinery. RIP140 (receptor interacting protein with a molecular weight of 140 kDa) is a widely expressed corepressor that has the potential to inhibit the transcriptional activity of most, if not all nuclear receptors. Mice devoid of RIP140 indicate that it plays a crucial role in female fertility and in adipose biology. It is essential in the ovary for ovulation, specifically oocyte release but not luteinisation of mature follicles. Our goal is to identify the key nuclear receptor(s) and their target genes responsible for ovulation.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Daucane phytoestrogens: a structure-activity study.

The estrogenic activity of a series of analogues of the daucane ester ferutinin (1a) modified at the acyl moiety was investigated in a yeast screen containing the human estrogen receptor alpha. Rather strict structure-activity relationships were observed. Thus, while the parent polyol (jaeschkeanadiol, 2a) was inactive, the presence of a p-hydroxybenzoyl moiety was necessary for activity in the yeast screen. Homologation and vinylation were both detrimental for activity, as were methylation of the p-hydroxyl substituent and the introduction of oxygen functions on the adjacent carbons.

Benzoates↗

PubMed2002

Embryo transfer experiments and ovarian transplantation identify the ovary as the only site in which nuclear receptor interacting protein 1/RIP140 action is crucial for female fertility.

Spatial and temporal regulation of gene expression by a number of different nuclear receptors is critical in female reproduction. In this study we investigated whether the nuclear receptor corepressor nuclear receptor interacting protein 1 (Nrip1)/RIP140, which is essential for ovulation, is also required for postovulatory events, leading to pregnancy and parturition. Expression analysis indicated that Nrip1 is present in the uterus in stromal and glandular epithelial cells, primary decidual cells, and subsequently in differentiating decidual cells at the anti-mesometrial side of the implantation site. It also indicated a temporal regulation of Nrip1 in the corpora lutea at different stages of pregnancy, with increased levels at midgestation at approximately d 9.5 postcoitum (pc). By performing both embryo and ovarian transfer experiments we demonstrate that, provided the block to ovulation is by-passed, Nrip1(-/-) mice are capable of establishing and maintaining pregnancies. However, although the majority of offspring derived from ovarian transplantation survived, approximately 50% of embryos were resorbed by d 13.5 pc after embryo transfer, and the majority of pups were stillborn or died soon thereafter. Thus, although Nrip1 is differentially expressed in the reproductive tract, we conclude that the ovary is the only site in which its action is essential for fertility, with a crucial role in ovulation and a secondary role in the maintenance of pregnancy.

Adaptor Proteins, Signal Transducing↗