Expression of guanylyl cyclase-B (GC-B/NPR2) receptors in normal human fetal pituitaries and human pituitary adenomas implicates a role for C-type natriuretic peptide.
C-type natriuretic peptide (CNP/Nppc) is expressed at high levels in the anterior pituitary of rats and mice and activates guanylyl cyclase B receptors (GC-B/Npr2) to regulate hormone secretion. Mutations in NPR2/Npr2 can cause achondroplasia, GH deficiency, and female infertility, yet the normal expression profile within the anterior pituitary remains to be established in humans. The current study examined the expression profile and transcriptional regulation of NPR2 and GC-B protein in normal human fetal pituitaries, normal adult pituitaries, and human pituitary adenomas using RT-PCR and immunohistochemistry. Transcriptional regulation of human NPR2 promoter constructs was characterized in anterior pituitary cell lines of gonadotroph, somatolactotroph, and corticotroph origin. NPR2 was detected in all human fetal and adult pituitary samples regardless of age or sex, as well as in all adenoma samples examined regardless of tumor origin. GC-B immunoreactivity was variable in normal pituitary, gonadotrophinomas, and somatotrophinomas. Maximal transcriptional regulation of the NPR2 promoter mapped to a region within -214 bp upstream of the start site in all anterior pituitary cell lines examined. Electrophoretic mobility shift assays revealed that this region contains Sp1/Sp3 response elements. These data are the first to show NPR2 expression in normal human fetal and adult pituitaries and adenomatous pituitary tissue and suggest a role for these receptors in both pituitary development and oncogenesis, introducing a new target to manipulate these processes in pituitary adenomas.
Endocrine Signalling Group, Veterinary Basic Sciences, University of London, Royal College Street, London NW1 0TU, UK.
Iain R
IR
Thompson
Annisa N
AN
Chand
Peter J
PJ
King
Olaf
O
Ansorge
Niki
N
Karavitaki
Ceri Alexander
CA
Jones
Dolkun
D
Rahmutula
David G
DG
Gardner
Vladimir
V
Zivkovic
Caroline P
CP
Wheeler-Jones
Imelda M
IM
McGonnell
Márta
M
Korbonits
Richard A
RA
Anderson
John A H
JA
Wass
Alan S
AS
McNeilly
Robert C
RC
Fowkes
D000236:Adenoma / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005333:Fetus / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D020098:Natriuretic Peptide, C-Type / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010902:Pituitary Gland / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics* / Q000378:metabolism; D000099242:Atrial Natriuretic Factor Receptor B
D020098:Natriuretic Peptide, C-Type; D017461:Receptors, Atrial Natriuretic Factor; D000099242:Atrial Natriuretic Factor Receptor B