RRC ID 72468
Author Parakh TN, Hernandez JA, Grammer JC, Weck J, Hunzicker-Dunn M, Zeleznik AJ, Nilson JH.
Title Follicle-stimulating hormone/cAMP regulation of aromatase gene expression requires beta-catenin.
Journal Proc Natl Acad Sci U S A
Abstract Estrogens profoundly influence the physiology and pathology of reproductive and other tissues. Consequently, emphasis has been placed on delineating the mechanisms underlying regulation of estrogen levels. Circulating levels of estradiol in women are controlled by follicle-stimulating hormone (FSH), which regulates transcription of the aromatase gene (CYP19A1) in ovarian granulosa cells. Previous studies have focused on two downstream effectors of the FSH signal, cAMP and the orphan nuclear receptor steroidogenic factor-1 (NR5A1). In this report, we present evidence for beta-catenin (CTNNB1) as an essential transcriptional regulator of CYP19A1. FSH induction of select steroidogenic enzyme mRNAs, including Cyp19a1, is enhanced by beta-catenin. Additionally, beta-catenin is present in transcription complexes assembled on the endogenous gonad-specific CYP19A1 promoter, as evidenced by chromatin immunoprecipitation assays. Transient expression and RNAi studies demonstrate that FSH- and cAMP-dependent regulation of this promoter is sensitive to alterations in the level of beta-catenin. The stimulatory effect of beta-catenin is mediated through functional interactions with steroidogenic factor-1 that involve four acidic residues within its ligand-binding domain, mutation of which attenuates FSH/cAMP-induced Cyp19a1 mRNA accumulation. Together, these data demonstrate that beta-catenin is essential for FSH/cAMP-regulated gene expression in the ovary, identifying a central and previously unappreciated role for beta-catenin in estrogen biosynthesis, and a potential broader role in other aspects of follicular maturation.
Volume 103(33)
Pages 12435-40
Published 2006-8-15
DOI 10.1073/pnas.0603006103
PII 0603006103
PMID 16895991
PMC PMC1533882
MeSH Animals Aromatase / genetics Aromatase / metabolism* Cells, Cultured Cholesterol Side-Chain Cleavage Enzyme / genetics Cholesterol Side-Chain Cleavage Enzyme / metabolism Cyclic AMP / metabolism* Estradiol / blood Female Follicle Stimulating Hormone / metabolism* Gene Expression Regulation, Enzymologic* Granulosa Cells / cytology Granulosa Cells / physiology Humans Ovary / cytology Ovary / physiology Phosphoproteins / genetics Phosphoproteins / metabolism Promoter Regions, Genetic RNA, Messenger / metabolism RNA, Small Interfering / genetics RNA, Small Interfering / metabolism Rats Rats, Sprague-Dawley Steroidogenic Factor 1 beta Catenin / metabolism*
IF 9.412
Human and Animal Cells KGN(RCB1154)