Expression of ACTH receptor pathway genes in glucose-dependent insulinotrophic peptide (GIP)-dependent Cushing's syndrome.
OBJECTIVE
The molecular mechanisms responsible for glucose-dependent insulinotrophic peptide receptor or gastric inhibitory polypeptide receptor (GIPR) ectopic expression and function in GIP-dependent Cushing's syndrome (CS) are still unknown. GIPR presumably acts, like the ACTH receptor (ACTHR), through the Gs protein/cyclic AMP/protein kinase A (PKA) pathway to stimulate steroidogenesis. We studied the expression of several genes involved in this pathway in the adrenal tissues of patients with GIP-dependent CS.


METHODS
RNA was extracted from adrenal tissues from nine patients with GIP-dependent CS [seven ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH), two adenomas], two control whole adult adrenals, two fasciculata cell-enriched preparations from normal adrenals, seven patients with Cushing's disease (CD) and two normal pancreas. Multiplex reverse transcriptase polymerase chain reaction (RT-PCR) evaluated the expression of GIPR, ACTHR, SF-1, Nur77, DAX-1, CYP11A, 3beta-HSD, CYP21, CREB and CREM genes.


RESULTS
GIPR mRNA was overexpressed in all GIP-dependent cases. In normal adrenals and in the adrenal tissues from patients with CD, minimal amounts of GIPR mRNA were detected. ACTHR mRNA expression was observed in all GIP-dependent adrenal tissues. The expression of steroidogenic enzymes and some specific and ubiquitous transcription factors (TFs) involved in the ACTHR cascade was significantly reduced.


CONCLUSIONS
Our results indicate that the expression of ACTHR and other genes located downstream in the ACTHR cascade, including steroidogenic enzymes genes and some transcription factors, are relatively suppressed in GIP-dependent CS. Although the expression of aberrant receptors plays an important role in steroidogenesis and initiation of cell proliferation, additional genetic events might occur, altering the activity of the ACTHR pathway.
Antonini
Sonir R
SR
Laboratory of Endocrine Pathophysiology, Research Centre, Hotel-Dieu du Centre Hospitalier de l'Universite de Montreal (CHUM), Montreal, Quebec, Canada.
Baldacchino
Valérie
V
Tremblay
Johanne
J
Hamet
Pavel
P
Lacroix
André
A
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics; D000302:Adrenal Cortex / Q000378:metabolism*; D000328:Adult; D050882:CREB-Binding Protein / Q000235:genetics; D016022:Case-Control Studies; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics; D003480:Cushing Syndrome / Q000235:genetics* / Q000378:metabolism; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010179:Pancreas / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis*; D018043:Receptors, Corticotropin / Q000235:genetics* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D013255:Steroid 21-Hydroxylase / Q000235:genetics; D054339:Steroidogenic Factor 1; D014157:Transcription Factors / Q000235:genetics
C497410:CREM protein, human; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C539965:NR0B1 protein, human; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D018043:Receptors, Corticotropin; D018160:Receptors, Cytoplasmic and Nuclear; D011964:Receptors, Gastrointestinal Hormone; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D012097:Repressor Proteins; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; D051786:Cyclic AMP Response Element Modulator; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor; D015096:3-Hydroxysteroid Dehydrogenases; D013255:Steroid 21-Hydroxylase; D002786:Cholesterol Side-Chain Cleavage Enzyme; D050882:CREB-Binding Protein