Jun proteins modulate the ovary-specific promoter of aromatase gene in ovarian granulosa cells via a cAMP-responsive element

Ghosh, Sagar; Wu, Yimin; Li, Rong; Hu, Yanfen

doi:10.1038/sj.onc.1208415

Cited by 39 publications

(30 citation statements)

References 48 publications

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“…The same effect was observed by overexpression of JunB [66]. Since these factors are transiently induced by forskolin, the authors suggested that they may be responsible for the delayed induction of aromatase.…”

Section: 3c Kinetics Of Aromatase Expressionmentioning

confidence: 62%

Aromatase expression in the ovary: Hormonal and molecular regulation

2008

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Summary-Estrogens are synthesized by the aromatase enzyme encoded by the Cyp19a1 gene, which contains an unusually large regulatory region. In most mammals, aromatase expression is under the control of two distinct promoters a gonad-and a brain-specific promoter. In humans, this gene contains 10 tissue-specific promoters that are alternatively used in various cell types and tumors. Each promoter is regulated by a distinct set of regulatory sequences and transcription factors that bind to these specific sequences. The cAMP/PKA/CREB pathway is considered to be the primary signaling cascade through which the gonad Cyp19 promoter is regulated. Very interestingly, in rat luteal cells, the proximal promoter is not controlled in a cAMP dependent manner. Strikingly, these cells express aromatase at high levels similar to those found in preovulatory follicles, suggesting that alternative and powerful mechanisms control aromatase expression in luteal cells and that the rat corpus luteum represents an important paradigm for understanding alternative controls of the aromatase gene. Here, the molecular and cellular mechanisms controlling the expression of the aromatase gene in granulosa and luteal cells are discussed.

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Section: 3c Kinetics Of Aromatase Expressionmentioning

confidence: 62%

Aromatase expression in the ovary: Hormonal and molecular regulation

2008

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“…Here, we showed that PGE 2 stimulated binding of c-Jun and ATF2 to aromatase PI.3/PII and that the binding coincided with peak phosphorylation and, therefore, peak transactivational activity of the proteins. Ghosh et al (37) have identified the CRE element of aromatase PII as the c-Jun binding site in granulosa cells; however, c-Jun represses rather than promotes aromatase expression in those cells. Our preliminary results suggested that ATF2 and c-Jun bound to the same element in BAFs (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E2 Induces Breast Cancer–Related Aromatase Promoters via Activation of p38 and c-Jun NH2-Terminal Kinase in Adipose Fibroblasts

et al. 2007

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Aromatase is the key enzyme for estrogen biosynthesis. A distal promoter, PI.4, maintains baseline levels of aromatase in normal breast adipose tissue. In contrast, malignant breast epithelial cells secrete prostaglandin E 2 (PGE 2 ), which stimulates aromatase expression via proximal promoters PI.3/PII in a cyclic AMP (cAMP)-and protein kinase C (PKC)-dependent manner in adjacent breast adipose fibroblasts (BAF), leading to increased local concentrations of estrogen. Although an effective treatment for breast cancer, aromatase inhibitors indiscriminately abolish estrogen synthesis in all tissues, causing major side effects. To identify drug targets to selectively block aromatase and estrogen production in breast cancer, we investigated PGE 2 -stimulated signaling pathways essential for aromatase induction downstream of cAMP and PKC in human BAFs. Here, we show that PGE 2 or its surrogate hormonal mixture dibutyryl cAMP (Bt 2 cAMP) + phorbol diacetate (PDA) stimulated the p38, c-jun NH 2 -terminal kinase (JNK)-1, and extracellular signalregulated kinase (ERK) mitogen-activated protein kinase pathways. Inhibition or small interfering RNA-mediated knockdown of p38 or JNK1, but not ERK, inhibited PGE 2 -or Bt 2 cAMP + PDA-induced aromatase activity and expression via PI.3/PII. Conversely, overexpression of wildtype p38A or JNK1 enhanced PGE 2 -stimulated aromatase expression via PII. PGE 2 or Bt 2 cAMP + PDA stimulated c-Jun and activating transcription factor-2 (ATF2) phosphorylation and binding to the PI.3/PII region. Specific activation of protein kinase A (PKA) or EPAC with cAMP analogues stimulated p38 and JNK1; however, only PKAactivating cAMP analogues induced aromatase expression. The PKC activator PDA effectively stimulated p38 and JNK1 phosphorylation but not aromatase expression. Taken together, PGE 2 activation of p38 and JNK1 via PKA and PKC is necessary for aromatase induction in BAFs, and p38 and JNK1 are potential new drug targets for tissue-specific ablation of aromatase expression in breast cancer. [Cancer Res 2007;67(18):8914-22]

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“…These include steroidogenic factor 1 (SF-1), CREB transcription factor family, Snail/Slug proteins, and several orphan nuclear receptors (Zhou and Chen, 1999;Chen et al, 2001;Richards, 2001;Simpson et al, 2002). In addition, Jun proteins, which interact with BRCA1 (Hu and Li, 2002), bind to the PII promoter of the aromatase gene and repress its transcriptional activity in KGN cells (Ghosh et al, 2005). Thus, it is conceivable that BRCA1 may be recruited to the I.3/PII promoters via its interaction with one or more site-specific transcriptional repressors.…”

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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Jun proteins modulate the ovary-specific promoter of aromatase gene in ovarian granulosa cells via a cAMP-responsive element

Cited by 39 publications

References 48 publications

Aromatase expression in the ovary: Hormonal and molecular regulation

Aromatase expression in the ovary: Hormonal and molecular regulation

Prostaglandin E2 Induces Breast Cancer–Related Aromatase Promoters via Activation of p38 and c-Jun NH2-Terminal Kinase in Adipose Fibroblasts

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

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