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Cyclic adenosine 3',5'-monophosphate-elevating agents inhibit transforming growth factor-beta-induced

Meinhard Schiller1, Frank Verrecchia, Alain Mauviel

  • 1INSERM U532, Institut de Recherche sur la Peau, Université Paris VII, Hôpital Saint-Louis, F-75010 Paris, France.

Oncogene
|December 5, 2003
PubMed

Insights

Cyclic adenosine monophosphate (cAMP) signaling inhibits transforming growth factor-beta (TGF-beta) by disrupting SMAD protein interactions with coactivators. This pathway affects gene transactivation, impacting cellular responses in keratinocytes.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Transforming growth factor-beta (TGF-beta) signaling has dual roles in cancer, acting as both a tumor suppressor and promoter.
  • SMAD proteins are key mediators of TGF-beta receptor signals, regulating target gene transcription.
  • Interactions with other signaling pathways modulate TGF-beta's cellular effects.

Purpose of the Study:

  • To investigate the impact of cyclic adenosine 3',5'-monophosphate (cAMP) on SMAD-dependent signaling in HaCaT keratinocytes.
  • To elucidate the molecular mechanisms by which cAMP influences TGF-beta-induced gene transactivation.

Main Methods:

  • Utilized a SMAD3/4-dependent reporter construct and the plasminogen activator inhibitor-1 gene.
  • Employed cAMP-elevating agents (dibutyryl cAMP, isobutyl-methylxanthine, forskolin, prostaglandin E2) and protein kinase A (PKA) inhibitor H-89.
  • Assessed nuclear translocation, DNA binding of SMAD3/4, and interactions with coactivators CREB-binding protein (CBP) and p300.

Main Results:

  • cAMP-elevating agents repressed TGF-beta-induced SMAD-specific gene transactivation.
  • Inhibition of PKA blocked cAMP-mediated repression, while active PKA or CREB overexpression inhibited SMAD transactivation.
  • cAMP did not affect SMAD nuclear translocation or DNA binding but disrupted SMAD3-CBP/p300 interactions in a PKA-dependent manner.

Conclusions:

  • cAMP signaling suppresses TGF-beta/SMAD pathway activity in HaCaT keratinocytes.
  • The suppression mechanism involves PKA-dependent disruption of SMAD3 interaction with coactivators CBP and p300, mediated by CREB.
  • This crosstalk provides insight into the regulation of TGF-beta signaling by second messengers.

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