The human CYP19 (aromatase P450) gene: update on physiologic roles and genomic organization of promoters

Bulun, Serdar E.; Sebastian, Siby; Takayama, Ken‐ichi; Suzuki, Takashi; Sasano, Hironobu; Shozu, Makio

doi:10.1016/s0960-0760(03)00359-5

Cited by 289 publications

(216 citation statements)

References 13 publications

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“…Thus, it is unlikely that BRCA1 represses an upstream step that is common to the activation of these genes. Expression of aromatase in various tissues is largely conferred by transcription initiation from tissue-specific promoters as well as alternative splicing that involves a promoter-specific, noncoding exon I (Bulun et al, 2003) (Figure 4b). The elevated aromatase expression upon BRCA1 knockdown in the granulosa cells could be due to super-activation of the ovary-specific promoter(s) and/or activation of a different tissue-specific promoter that is otherwise dormant in ovarian granulosa cells.…”

Section: A Gene-and Promoter-specific Effect Of Brca1mentioning

confidence: 99%

Modulation of aromatase expression by BRCA1: a possible link to tissue-specific tumor suppression

Ghosh

Amleh

et al. 2005

Oncogene

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Mutations in BRCA1 increase risks of familial breast and ovarian cancers, particularly among premenopausal women. While BRCA1 plays an active role in DNA repair, this function alone may not be sufficient to explain why BRCA1-associated tumors predominantly occur in estrogen-responsive tissues. Aromatase is the rate-limiting enzyme in estrogen biosynthesis and a key target in breast cancer treatment. Aromatase expression in ovarian granulosa cells dictates levels of circulating estrogen in premenopausal women, and its aberrant overexpression in breast adipose tissues promotes breast cancer growth. Here, we show that BRCA1 modulates aromatase expression in ovarian granulosa cells and primary preadipocytes. The cyclic AMP-dependent expression of aromatase in ovarian granulosa cells is inversely correlated with the protein level of BRCA1. Importantly, transient knockdown of BRCA1 enhances aromatase expression in both ovarian granulosa cells and primary preadipocytes. We propose that BRCA1 deficiency in epithelial and certain nonepithelial cells may result in combined effects of aberrant estrogen biosynthesis and compromised DNA repair capability, which in turn may lead to specific cancers in the breast and ovary.

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Section: A Gene-and Promoter-specific Effect Of Brca1mentioning

confidence: 99%

Modulation of aromatase expression by BRCA1: a possible link to tissue-specific tumor suppression

Ghosh

Amleh

et al. 2005

Oncogene

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“…Expression of the aromatase gene is regulated by the tissuespecific activation of the multiplex promoter. In breast cancer tissues and cell lines, exon I arising from promoters (Ps) I.1, I.3, I.4, and I.7, and a 5Ј region of exon II arising from PII have been confirmed (9,(22)(23)(24)(25). Thus, it appears that the prototype estrogen-dependent breast cancer takes advantage of these promoters for aromatase expression.…”

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confidence: 96%

Activation of Aromatase Expression by Retinoic Acid Receptor-related Orphan Receptor (ROR) α in Breast Cancer Cells

Odawara¹,

Iwasaki²,

Horiguchi³

et al. 2009

Journal of Biological Chemistry

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Estrogen is a key regulator of the proliferation and differentiation of breast cancer cells. In addition to the estrogen supply from the ovary, estrogen is produced locally from androgen by aromatase. However, the regulation of aromatase gene expression in breast cancer has not yet been fully clarified. Retinoic acid receptor-related orphan receptor (ROR) ␣ plays an important role in the differentiation of many organs by regulating the transcription of target genes. Because aromatase and ROR␣ are expressed in breast cancer, the effect of ROR␣ on aromatase gene expression was studied. ROR␣ significantly augmented the expression of aromatase mRNA, particularly those containing exon I.4, in MCF7 cells, and aromatase activities in T47D and MCF7 cells. ROR␣ also stimulated the proliferation of these cells. Transient transfection-based reporter gene assays using the promoter at exon I.4 showed that ROR␣ augmented the transcription. A series of truncated mutation studies revealed that ROR␣ activated the transcription through ؊147 to ؉14 bp of the promoter I.4. Furthermore, ROR␣ bound to the fragment containing ؊119 to ؊107 bp of the promoter in vitro, indicating that this region may contain a novel ROR response element. Chromatin immunoprecipitation assay showed that ROR␣ bound to the region containing this site of the promoter I.4 in MCF7 cells. Moreover, we examined clinical samples and found a correlation between ROR␣ and aromatase expression. These results suggest that ROR␣ directly activates the aromatase expression to accelerate the local production of estrogen, which results in the proliferation of breast cancer cells.

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“…This gene encodes the cytochrome P450 enzyme aromatase, which catalyzes the irreversible conversion of androgens to estrogens (5). The CYP19A1 gene contains multiple promoters that dictate tissue-specific patterns of aromatase expression (6). In the ovary, expression of CYP19A1 is directed by the type II promoter (PII) that resides within the immediate 5Ј region flanking the translational start site (7).…”

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confidence: 99%

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

Parakh

Hernández

Grammer

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

152

109

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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 ␤-catenin (CTNNB1) as an essential transcriptional regulator of CYP19A1. FSH induction of select steroidogenic enzyme mRNAs, including Cyp19a1, is enhanced by ␤-catenin. Additionally, ␤-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 ␤-catenin. The stimulatory effect of ␤-catenin is mediated through functional interactions with steroidogenic factor-1 that involve four acidic residues within its ligand-binding domain, mutation of which attenuates FSH͞cAMP-induced Cyp19a1 mRNA accumulation. Together, these data demonstrate that ␤-catenin is essential for FSH͞cAMP-regulated gene expression in the ovary, identifying a central and previously unappreciated role for ␤-catenin in estrogen biosynthesis, and a potential broader role in other aspects of follicular maturation.ovary ͉ steroidogenic factor-1 ͉ granulosa cells ͉ steroidogenesis ͉ estrogen E strogens play a central role in regulating homeostatic and pathologic pathways. They influence fertility and sexual behavior, lipid metabolism, bone remodeling, and the development of various endocrine cancers (1). Ovarian follicles are the primary source of local and circulating estrogen in mammals (2). Synthesis of follicular estradiol depends on the coordinated actions of the pituitary gonadotropin hormones, folliclestimulating hormone (FSH) and luteinizing hormone, cytokines, and growth factors (3, 4).FSH induces estrogen biosynthesis by triggering cAMPdependent signaling cascades to regulate transcription of the CYP19A1 gene . This gene encodes the cytochrome P450 enzyme aromatase, which catalyzes the irreversible conversion of androgens to estrogens (5). The CYP19A1 gene contains multiple promoters that dictate tissue-specific patterns of aromatase expression (6). In the ovary, expression of CYP19A1 is directed by the type II promoter (PII) that resides within the immediate 5Ј region flanking the translational start site (7). PII is also pathologically activated in adipocytes in malignant breast tissue (8). Therefore, delineating mechanisms that contribute to follicular expression of CYP19A1 is essential for understanding how estrogen levels are regulated in health and disease.Among the numerous cis-acting elements identified within the CYP19A1...

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The human CYP19 (aromatase P450) gene: update on physiologic roles and genomic organization of promoters

Cited by 289 publications

References 13 publications

Modulation of aromatase expression by BRCA1: a possible link to tissue-specific tumor suppression

Modulation of aromatase expression by BRCA1: a possible link to tissue-specific tumor suppression

Activation of Aromatase Expression by Retinoic Acid Receptor-related Orphan Receptor (ROR) α in Breast Cancer Cells

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

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