Abstract
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.
Highlights
The particulate guanylyl cyclase (GC) receptors mediate the effects of natriuretic peptides, heat-stable enterotoxins, odor, and peptidase activity in a broad range of tissues by increasing the levels of cyclic guanosine 30,50-monophosphate
We have examined the mRNA expression of NPR2 in a range of human pituitary adenomas and normal human fetal and adult pituitaries, determined the transcriptional regulation of the human GC-B promoter in anterior pituitary cell lines, and established the localization of GC-B protein expression by immunohistochemistry in a range of human pituitary adenomas
Many previous studies have established the presence of the C-type natriuretic peptide (CNP) and its receptor, GC-B, in rat, mouse, and sheep pituitaries (Komatsu et al 1991, Konrad et al 1992, Minamino et al 1993, Yandle et al 1993, McArdle et al 1994, Herman et al 1996, Thompson et al 2009), yet the expression of GC-B in human pituitary tissue has not been reported
Summary
The particulate guanylyl cyclase (GC) receptors mediate the effects of natriuretic peptides, heat-stable enterotoxins, odor, and peptidase activity in a broad range of tissues by increasing the levels of cyclic guanosine 30,50-monophosphate (cGMP). Mice lacking the Npr gene, which encodes GC-B, are dwarf due to severe deficiency in the process of endochondral ossification and exhibit early lethality (Tamura et al 2004). These mice are GH deficient, implicating a potential pituitary phenotype. Mutations in the gene (natriuretic peptide precursor C (Nppc)) encoding CNP essentially phenocopy those in Npr (Chusho et al 2001), but to date, no mutations have been reported in the human NPPC gene. The role of GC-B receptors, or of CNP, in the anterior pituitary remains poorly understood
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