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NGF, cyclic AMP, and phorbol esters regulate oxytocin receptor gene transcription in SK-N-SH and MCF7 cells

T L Bale1, D M Dorsa

  • 1Department of Pharmacology, University of Washington, Box 357280, Seattle, WA 98195, USA. tbale@u.washington.edu

Brain Research. Molecular Brain Research
|April 29, 1998
PubMed

Insights

Estrogen is not the only regulator of oxytocin receptor (OTR) gene transcription. New promoter regions reveal cAMP and phorbol ester pathways, suggesting alternate mechanisms for OTR gene regulation.

Area of Science:

  • Molecular Endocrinology
  • Neuroendocrinology
  • Gene Regulation

Background:

  • Oxytocin receptor (OTR) gene transcription is primarily attributed to estrogen regulation.
  • Persistent OTR presence post-gonadectomy indicates alternative regulatory mechanisms.
  • Previous OTR promoter studies may have missed key regulatory elements.

Purpose of the Study:

  • To identify novel regulatory elements in the rat OTR gene's 5'-flanking DNA.
  • To investigate the role of cAMP and phorbol ester pathways in OTR gene transcription.
  • To elucidate alternative mechanisms regulating OTR gene expression beyond estrogen.

Main Methods:

  • Cloned and sequenced 4 kb of the rat OTR gene's 5'-flanking DNA.
  • Performed transfection experiments in MCF7 and SK-N-SH cells using various treatments (PMA, forskolin, NGF).
  • Conducted receptor binding assays and Western blot analyses to assess OTR density.
  • Utilized mutational analyses of identified regulatory elements (CRE, half-SRE).

Main Results:

  • Identified a novel promoter region containing CRE, AP-1, AP-2, AP-3, AP-4, ERE, and half-SRE sites.
  • Forskolin and PMA significantly induced OTR promoter transcription, with a synergistic 17-fold increase in MCF7 cells.
  • PMA and forskolin increased endogenous human oxytocin receptor density.
  • CRE and half-SRE sites act as enhancers, supporting forskolin and NGF effects on transcription, respectively.

Conclusions:

  • A novel region of the rat OTR promoter confers inducibility by cAMP and/or phorbol esters.
  • These findings suggest a significant role for Protein Kinase A (PKA) and/or Protein Kinase C (PKC) pathways in OTR gene regulation.
  • Provides evidence for non-estrogen-dependent regulation of oxytocin receptor gene transcription.

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