Follicle-stimulating hormone/cAMP regulation of aromatase gene expression requires beta-catenin.
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.
Parakh
Tehnaz N
TN
School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA.
Hernandez
Jennifer A
JA
Grammer
Jean C
JC
Weck
Jennifer
J
Hunzicker-Dunn
Mary
M
Zeleznik
Anthony J
AJ
Nilson
John H
JH
D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D004958:Estradiol / Q000097:blood; D005260:Female; D005640:Follicle Stimulating Hormone / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006107:Granulosa Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D010053:Ovary / Q000166:cytology / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D054339:Steroidogenic Factor 1; D051176:beta Catenin / Q000378:metabolism*; D000098682:Steroidogenic Acute Regulatory Protein
C515057:NR5A1 protein, human; D010750:Phosphoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054339:Steroidogenic Factor 1; D051176:beta Catenin; D000098682:Steroidogenic Acute Regulatory Protein; C515060:steroidogenic factor 1, rat; D004958:Estradiol; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP; D001141:Aromatase; D002786:Cholesterol Side-Chain Cleavage Enzyme