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Molecular evidence of functional progesterone withdrawal in human myometrium

Author

Listed:
  • Lubna Nadeem

    (Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital)

  • Oksana Shynlova

    (Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital
    University of Toronto)

  • Elzbieta Matysiak-Zablocki

    (Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital)

  • Sam Mesiano

    (Case Western Reserve University)

  • Xuesen Dong

    (University of Toronto
    Vancouver Prostate Centre, University of BC)

  • Stephen Lye

    (Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital
    University of Toronto
    Department of Physiology University of Toronto)

Abstract

Progesterone suppresses uterine contractility acting through its receptors (PRA/B). The mechanism by which human labour is initiated in the presence of elevated circulating progesterone has remained an enigma since Csapo first theorized of a functional withdrawal of progesterone in 1965. Here we report that in vitro progesterone-liganded nuclear PRB forms a complex including JUN/JUN homodimers and P54nrb/Sin3A/HDAC to repress transcription of the key labour gene, Cx43. In contrast, unliganded PRA paradoxically activates Cx43 transcription by interacting with FRA2/JUND heterodimers. Furthermore, we find that while nuclear progesterone receptor (PR) is liganded during human pregnancy, it becomes unliganded during both term and preterm labour as a result of increased expression of the progesterone-metabolizing enzyme 20α HSD and reduced nuclear progesterone levels. Our data provide a mechanism by which human labour can occur in the presence of elevated circulating progesterone and suggests non-metabolizable progestogen might represent an alternative new therapeutic approach to preterm birth prevention.

Suggested Citation

  • Lubna Nadeem & Oksana Shynlova & Elzbieta Matysiak-Zablocki & Sam Mesiano & Xuesen Dong & Stephen Lye, 2016. "Molecular evidence of functional progesterone withdrawal in human myometrium," Nature Communications, Nature, vol. 7(1), pages 1-9, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11565
    DOI: 10.1038/ncomms11565
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