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Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone

C Jonat1, H J Rahmsdorf, K K Park

  • 1Kernforschungszentrum Karlsruhe, Federal Republic of Germany.

Cell
|September 21, 1990
PubMed

Insights

Glucocorticoid hormones inhibit collagenase I expression by directly interacting with AP-1, a key transcription factor. This novel mechanism down-modulates AP-1 activity without requiring new protein synthesis or DNA binding.

Area of Science:

  • Molecular Biology
  • Endocrinology
  • Cancer Research

Background:

  • Glucocorticoid hormones possess anti-inflammatory and anti-tumor promoting properties.
  • These hormones significantly reduce the expression of extracellular proteases, such as collagenase I.
  • Collagenase I expression is regulated by transcription factors, including AP-1.

Purpose of the Study:

  • To elucidate the novel mechanism by which glucocorticoid hormones inhibit collagenase I gene expression.
  • To investigate the role of AP-1 transcription factor in mediating glucocorticoid hormone effects.
  • To explore the interaction between hormone receptors and AP-1.

Main Methods:

  • Analysis of basal and induced collagenase I transcription.
  • Investigation of AP-1 binding and trans-activating function.
  • Hormone receptor dependency and DNA binding assays.
  • Coprecipitation experiments to detect protein-protein interactions.
  • Fos or Jun overexpression studies.

Main Results:

  • Glucocorticoid hormones inhibit both basal and induced collagenase I transcription.
  • The inhibitory mechanism involves interference with AP-1, independent of protein synthesis or hormone receptor DNA binding.
  • Effective inhibition occurs at low hormone doses, down-modulating AP-1's trans-activating function.
  • Coprecipitation suggests a direct interaction between AP-1 and the hormone receptor.
  • Overexpression of Fos or Jun inhibits hormone-dependent gene expression.

Conclusions:

  • Glucocorticoid hormones directly interact with AP-1 to suppress collagenase I expression.
  • This interaction is a novel mechanism for gene regulation, distinct from typical hormone-mediated gene activation.
  • The findings provide insights into the molecular basis of glucocorticoid action in inflammation and tumor promotion.

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