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Novel protein kinase C-epsilon inhibits human CYP11B2 gene expression through ERK1/2 signalling pathway and JunB

Jean-Guy LeHoux1, Andrée Lefebvre

  • 1Department of Biochemistry, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada, J1H 5N4. jean-guy.lehoux@usherbrooke.ca

Journal of Molecular Endocrinology
|February 8, 2006
PubMed

Insights

Protein Kinase C epsilon (PKCepsilon) inhibits CYP11B2 transcription via the p44/42 MAP kinase (MAPK) pathway and JunB in H295R cells, revealing a novel regulatory mechanism.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cell Signaling

Background:

  • H295R cells express three diacylglycerol (DAG)-dependent protein kinase Cs (PKCs): PKCalpha, PKCepsilon, and PKCtheta.
  • Angiotensin II (Ang II) is known to activate p44/42 MAPK, but the specific PKC isoforms involved and their downstream effects on CYP11B2 regulation were unclear.

Purpose of the Study:

  • To investigate the role of DAG-dependent PKCs in Ang II-induced p44/42 MAPK activation.
  • To elucidate the pathway mediating Ang II's effect on CYP11B2 gene regulation in H295R cells.

Main Methods:

  • Utilized PKC inhibitors (Bisindolylmaleimide 1, Gö6976) and overexpression of wild-type and dominant-negative ERK1/2.
  • Employed adenoviral vectors to express constitutively active (ca) PKCepsilon and assessed MEK1/2 and p44/42 MAPK activation.
  • Investigated the impact of caPKCepsilon and MEK1 inhibition (PD98059) on aldosterone synthase mRNA levels and JunB protein expression.
  • Analyzed the effect of JunB overexpression on CYP11B2 promoter activity.

Main Results:

  • PKCepsilon, not PKCalpha, mediated Ang II-induced p44/42 MAPK activation.
  • Overexpression of ERK1/2 reduced CYP11B2 activity, while dominant-negative mutants increased it.
  • caPKCepsilon activated MEK1/2 and p44/42 MAPK, inhibited aldosterone synthase mRNA, and increased JunB protein.
  • JunB overexpression abolished Ang II-induced CYP11B2 promoter activity.

Conclusions:

  • PKCepsilon acts as the key mediator of Ang II signaling in H295R cells.
  • The PKCepsilon/p44/42 MAPK/JunB pathway negatively regulates CYP11B2 transcription.
  • This study identifies a novel inhibitory mechanism for CYP11B2 expression involving PKCepsilon and JunB.

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