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Expression of ACTH receptor pathway genes in glucose-dependent insulinotrophic peptide (GIP)-dependent Cushing's

Sonir R Antonini1, Valérie Baldacchino, Johanne Tremblay

  • 1Laboratory of Endocrine Pathophysiology, Research Centre, Hotel-Dieu du Centre Hospitalier de l'Universite de Montreal (CHUM), Montreal, Quebec, Canada.

Clinical Endocrinology
|January 13, 2006
PubMed
Abstract

Insights

Glucose-dependent insulinotropic polypeptide receptor (GIPR) is overexpressed in GIP-dependent Cushing's syndrome (CS). However, ACTH receptor (ACTHR) and downstream genes are suppressed, suggesting additional genetic events in CS pathogenesis.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Genetics

Background:

  • Ectopic expression of glucose-dependent insulinotropic polypeptide receptor (GIPR) in GIP-dependent Cushing's syndrome (CS) is not well understood.
  • The GIPR pathway is presumed to activate steroidogenesis via the Gs protein/cyclic AMP/protein kinase A (PKA) pathway, similar to the ACTH receptor (ACTHR).

Purpose of the Study:

  • To investigate the molecular mechanisms of GIPR ectopic expression and function in GIP-dependent CS.
  • To analyze the expression of genes in the Gs protein/cyclic AMP/PKA pathway within adrenal tissues of GIP-dependent CS patients.

Main Methods:

  • RNA extracted from adrenal tissues of nine GIP-dependent CS patients (seven AIMAH, two adenomas), controls, and Cushing's disease (CD) patients.
  • Multiplex RT-PCR used to evaluate expression of GIPR, ACTHR, SF-1, Nur77, DAX-1, CYP11A, 3beta-HSD, CYP21, CREB, and CREM genes.

Main Results:

  • GIPR mRNA was significantly overexpressed in all GIP-dependent CS cases.
  • ACTHR mRNA was detected in all GIP-dependent adrenal tissues.
  • Expression of steroidogenic enzymes and transcription factors in the ACTHR cascade was significantly reduced.

Conclusions:

  • GIPR is aberrantly expressed in GIP-dependent CS.
  • ACTHR and downstream genes, including steroidogenic enzymes and transcription factors, are suppressed in GIP-dependent CS.
  • Additional genetic events beyond aberrant receptor expression likely contribute to the altered ACTHR pathway activity in CS.

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