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

Oncogene volume 24, pages 2236–2246 (2005)Cite this article

Abstract

Estrogen is critical to both normal mammary gland and breast cancer development. Circulating levels of estrogen in premenopausal women are primarily determined by the action of aromatase in ovarian granulosa cells that converts testosterone to estradiol. In the current study, we unraveled an important role of Jun proteins in modulating ovary-specific aromatase expression. Ectopic expression of the Jun proteins in a human granulosa cell line significantly inhibited an ovary-specific promoter (PII) of the aromatase gene, whereas expression of dominant-negative mutants of Jun led to increased promoter activity. The Jun-mediated repression was specific to the aromatase promoter, as Jun proteins stimulated known AP1-responsive promoters in the same cellular context. Both the activation and basic leucine zipper domains of Jun were required for the transcriptional repression. Electrophoretic gel mobility assay showed that endogenous Jun proteins bound to a functionally important cAMP-responsive element (CRE) in the PII promoter-proximal region. Alteration of the CRE-like site impaired both the cAMP-responsive transcriptional activation and Jun-mediated repression. Furthermore, chromatin immunoprecipitation indicated the presence of cJun at the proximal region of the native PII promoter. Taken together, our work suggests that Jun proteins may attenuate estrogen biosynthesis by directly downregulating transcription of the aromatase gene in ovarian granulosa cells.

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Acknowledgements

We thank Drs B Vogelstein, R Muller, R Uht, and LK Christenson for generously providing regents. We thank Dr Asma Amleh for critical reading of the manuscript; and members of the Li and Hu laboratories for stimulating discussion. This work was supported by grants to RL from the National Institutes of Health (CA093506), and to YH from the Department of Defense Breast Cancer Research Program (DAMD17-03-1-0398).

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  1. Department of Biochemistry and Molecular Genetics, School of Medicine, University of Virginia, Charlottesville, VA, 22908, USA

    Sagar Ghosh, Yimin Wu, Rong Li & Yanfen Hu

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  1. Sagar Ghosh
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Correspondence to Rong Li or Yanfen Hu.

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Ghosh, S., Wu, Y., Li, R. et al. Jun proteins modulate the ovary-specific promoter of aromatase gene in ovarian granulosa cells via a cAMP-responsive element. Oncogene 24, 2236–2246 (2005). https://doi.org/10.1038/sj.onc.1208415

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