Pin1 facilitates the phosphorylation-dependent ubiquitination of SF-1 to regulate gonadotropin beta-subunit gene transcription.
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. Herein, we demonstrate that Pin1 is required for both basal and GnRH-induced gonadotropin beta-subunit gene transcription, through interactions with the transcription factors SF-1, Pitx1, and Egr-1. Pin1 activates transcription of the gonadotropin beta-subunit genes synergistically with these transcription factors, either by modulating their stability or by increasing their protein-protein interactions. Notably, we provide evidence that Pin1 is required for the Ser203 phosphorylation-dependent ubiquitination of SF-1, which facilitates SF-1-Pitx1 interactions and therefore results in an enhancement of SF-1 transcriptional activity. Furthermore, we demonstrate that in gonadotrope cells, sufficient levels of activated Pin1 are maintained through transcriptional and posttranslational regulation by GnRH-induced signaling cascades. Our results suggest that Pin1 functions as a novel player in GnRH-induced signal pathways and is involved in gonadotropin beta-subunit gene transcription by modulating the activity of various specific transcription factors.
Luo
Zhuojuan
Z
Technion-Israel Institute of Technology, Haifa 32000, Israel.
Wijeweera
Andrea
A
Oh
Yingzi
Y
Liou
Yih-Cherng
YC
Melamed
Philippa
P
D000818:Animals; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism* / Q000494:pharmacology; D006062:Gonadotropins / Q000235:genetics*; D051379:Mice; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D051761:Paired Box Transcription Factors / Q000378:metabolism; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D054339:Steroidogenic Factor 1 / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D054875:Ubiquitination / Q000502:physiology
D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D006062:Gonadotropins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D051761:Paired Box Transcription Factors; D034741:RNA, Small Interfering; D054339:Steroidogenic Factor 1; C101485:homeobox protein PITX1; C515058:steroidogenic factor 1, mouse; D007987:Gonadotropin-Releasing Hormone; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse