The Roles of PIN1 in the Pituitary Ganadotropes

Abstract

Pin1 is a peptidyl-prolyl cis/trans isomerase which catalyzes the isomerization of phosphorylated Ser/Thr-Pro peptide bonds. Pin1 knockout mice have marked abnormalities in their reproductive development and function. However, the molecular mechanisms underlying their reproductive defects are poorly understood. In this study, it has been demonstrated that Pin1 is required for both basal and GnRH-induced gonadotropin ß subunit gene transcription through physical and functional interactions with the transcription factors SF-1, Pitx1, and Egr-1. Pin1 activates transcription of the gonadotropin ß subunit genes synergistically with these transcription factors, either by modulating their stability or by increasing their protein¿protein interactions. Notably, it has been shown that Pin1 is required for the Ser 203 phosphorylation-dependent ubiquitination of SF-1, which facilitates SF-1¿Pitx1 interactions and therefore results in an enhancement of SF-1 transcriptional activity. It has also been demonstrated that in gonadotrope cells sufficient levels of activated Pin1 are maintained through transcriptional and post-translational regulation by GnRH-induced signaling cascades. These results suggest that Pin1 functions as a novel player in GnRH-induced signal pathways and is involved in gonadotropin ß subunit gene transcription by modulating the activity of various specific transcription factors. In addition, in this study it has been shown that Pin1 can complex with the aGSU gene transcription factors, c-Jun and ATF3, and increase the protein level of ATF3 in gonadotropes. These findings would lay the foundation for investigating whether Pin1 plays a role in transcriptional regulation of aGSU gene.