Follicle-stimulating hormone/cAMP regulation of aromatase gene expression requires β-catenin

doi:10.1073/pnas.0603006103

Follicle-stimulating hormone/cAMP regulation of aromatase gene expression requires β-catenin

*School of Molecular Biosciences, Washington State University, Pullman, WA 99164;
^†Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106; and
^‡Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA 15621

Edited by Lutz Birnbaumer, National Institutes of Health, Research Triangle Park, NC, and approved June 28, 2006 (received for review April 12, 2006)

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 β-catenin (CTNNB1) as an essential transcriptional regulator of CYP19A1. FSH induction of select steroidogenic enzyme mRNAs, including Cyp19a1, is enhanced by β-catenin. Additionally, β-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 β-catenin. The stimulatory effect of β-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 β-catenin is essential for FSH/cAMP-regulated gene expression in the ovary, identifying a central and previously unappreciated role for β-catenin in estrogen biosynthesis, and a potential broader role in other aspects of follicular maturation.

Footnotes

^§To whom correspondence should be addressed at:
School of Molecular Biosciences, Fulmer 639A, Washington State University, Pullman, WA 99164-4660.
E-mail: jhn{at}wsu.edu
Author contributions: T.N.P. and J.H.N. designed research; T.N.P., J.A.H., J.C.G., and J.W. performed research; A.J.Z. contributed new reagents/analytic tools; T.N.P., J.A.H., J.C.G., J.W., M.H.-D., and J.H.N. analyzed data; T.N.P. wrote the paper; and J.A.H., J.C.G., J.W., M.H.-D., A.J.Z., and J.H.N. edited the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations

Cyp11a1,

cytochrome P450 side-chain-cleavage enzyme;

Cyp19a1,

cytochrome P450 aromatase;

FSH,

follicle-stimulating hormone;

GC,

granulosa cell;

LRH1,

liver receptor homologue-1;

SF1,

steroidogenic factor-1;

STAR,

steroidogenic acute regulatory protein;

vpm,

virus particles per milliliter.
Freely available online through the PNAS open access option.