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Repression of NFAT3 transcriptional activity by estrogen receptors

X Qin1, X-H Wang, Z-H Yang

  • 1Department of Molecular Oncology, Beijing Institute of Biotechnology, 27 Tai-Ping Lu Rd, Beijing 100850, China.

Cellular and Molecular Life Sciences : CMLS
|August 1, 2008
PubMed

Insights

Estrogen receptors alpha and beta (ERalpha and ERbeta) suppress Nuclear Factor of Activated T cells 3 (NFAT3) activity. Estrogen enhances this suppression, revealing a key regulatory role for ER in NFAT3 transcriptional activity.

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Endocrinology

Background:

  • Nuclear factor of activated T cells 3 (NFAT3) is involved in critical biological processes including breast cancer and cardiac hypertrophy.
  • The precise mechanisms by which protein factors regulate NFAT3 transcriptional activity remain largely unknown.
  • Estrogen receptors (ERs) are key regulators of cellular functions, but their interaction with NFAT3 is not well characterized.

Purpose of the Study:

  • To investigate the role of estrogen receptors alpha and beta (ERalpha and ERbeta) in modulating Nuclear Factor of activated T cells 3 (NFAT3) transcriptional activity.
  • To determine if estrogen influences the interaction between ERs and NFAT3.
  • To elucidate the molecular mechanisms underlying ER-mediated regulation of NFAT3.

Main Methods:

  • Overexpression and knockdown of ERalpha and ERbeta in cellular models.
  • Assays to measure NFAT3 transcriptional activity.
  • Co-immunoprecipitation to assess protein-protein interactions between ERs and NFAT3.
  • Chromatin immunoprecipitation to evaluate ERalpha recruitment to NFAT3 target gene promoters.
  • Site-directed mutagenesis to study the effect of ERalpha phosphorylation on NFAT3 activity.

Main Results:

  • Overexpression of ERalpha and ERbeta suppressed NFAT3 transcriptional activity, while their knockdown enhanced it.
  • Estrogen treatment further potentiated the inhibitory effect of ERs on NFAT3-dependent transcription.
  • ERalpha and ERbeta were found to interact with NFAT3 independently of standard NFAT activation.
  • ERalpha was demonstrated to bind to an NFAT3 target gene promoter.
  • Specific phosphorylation sites on ERalpha differentially modulated its effect on NFAT3 activity.

Conclusions:

  • Estrogen receptors alpha and beta play a significant inhibitory role in regulating NFAT3 transcriptional activity.
  • Estrogen amplifies the suppressive function of ERs on NFAT3.
  • ERalpha and ERbeta directly interact with NFAT3, suggesting a novel regulatory pathway.
  • These findings highlight a critical role for ER in controlling NFAT3-mediated biological processes.

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