scholarly journals 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

2012 ◽  
Vol 19 (4) ◽  
pp. 497-508 ◽  
Author(s):  
Iain R Thompson ◽  
Annisa N Chand ◽  
Peter J King ◽  
Olaf Ansorge ◽  
Niki Karavitaki ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Natriuretic Peptide ◽  
Cell Lines ◽  
Expression Profile ◽  
Guanylyl Cyclase ◽  
Pituitary Adenomas ◽  
Anterior Pituitary ◽  
Pituitary Cell ◽  
Human Pituitary ◽  
Normal Human

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.

scholarly journals C-type natriuretic peptide (CNP) effects in anterior pituitary cell lines: evidence for homologous desensitisation of CNP-stimulated cGMP accumulation in alpha T3-1 gonadotroph-derived cells

2000 ◽  
Vol 166 (1) ◽  
pp. 195-203 ◽  
Author(s):  
RC Fowkes ◽  
W Forrest-Owen ◽  
CA McArdle
Keyword(s):  
Natriuretic Peptide ◽  
Cell Lines ◽  
Guanylyl Cyclase ◽  
Anterior Pituitary ◽  
Phorbol Esters ◽  
Cell Types ◽  
Pituitary Cell ◽  
Anterior Pituitary Cell ◽  
Peptide Family ◽  
Rat Pituitary

C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family, has been found at its highest tissue concentrations in the anterior pituitary, where it is localised in gonadotrophs. Its specific guanylyl cyclase-containing receptor, GC-B, is also expressed on several anterior pituitary cell types, and CNP potently stimulates cGMP accumulation in rat pituitary cell cultures and pituitary cell lines. The mouse gonadotroph-derived alpha T3-1 cell line has been shown to express CNP as well as GC-B (but not GC-A) receptors, suggesting that CNP may well be an autocrine regulator of gonadotrophs. Comparing effects of three natriuretic peptides (atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and CNP) on cGMP accumulation in four pituitary cell lines (alpha T3-1, TtT-GF, AtT-20 and GH(3)) we find that CNP is most potent and effective in alpha T3-1 cells. In these cells, CNP-stimulated cGMP accumulation was found to desensitise during a 30 min exposure to CNP. Pretreatment with CNP for up to 6 h also caused a significant reduction in the ability of CNP to subsequently stimulate cGMP accumulation. This effect was receptor specific, because pretreatment with sodium nitroprusside (an activator of nitric oxide-sensitive guanylyl cyclase), or with ANP or BNP, did not cause desensitisation of CNP-stimulated cGMP accumulation. Protein kinase C activation with phorbol esters also inhibited CNP-stimulated cGMP accumulation and such inhibition was also seen in cells desensitised by pretreatment with CNP. Thus it appears that the endogenous GC-B receptors of alpha T3-1 cells are subject to both homologous and heterologous desensitisation, that the mechanisms underlying these forms of desensitisation are distinct, and that cGMP elevation alone is insufficient to desensitise GC-B receptors.

scholarly journals Selective Loss of MEG3 Expression and Intergenic Differentially Methylated Region Hypermethylation in the MEG3/DLK1 Locus in Human Clinically Nonfunctioning Pituitary Adenomas

2008 ◽  
Vol 93 (10) ◽  
pp. 4119-4125 ◽  
Author(s):  
Roger Gejman ◽  
Dalia L. Batista ◽  
Ying Zhong ◽  
Yunli Zhou ◽  
Xun Zhang ◽  
...  
Keyword(s):  
Pituitary Adenomas ◽  
Cell Types ◽  
Pituitary Cell ◽  
Differentially Methylated Region ◽  
Tumor Type ◽  
Cell Type ◽  
Rt Pcr ◽  
Human Pituitary ◽  
Nonfunctioning Pituitary Adenomas ◽  
Normal Human

Context: MEG3 is an imprinted gene encoding a novel noncoding RNA that suppresses tumor cell growth. Although highly expressed in the normal human pituitary, it is unknown which of the normal pituitary cell types and pituitary tumors express MEG3. Objectives: Our objectives were 1) to investigate cell-type- and tumor-type-specific expression of MEG3 in the human pituitary and 2) to investigate whether methylation in the intergenic differentially methylated region (IG-DMR) at the DLK1/MEG3 locus is involved in the loss of MEG3 expression in tumors. Design and Methods: RT-PCR, quantitative RT-PCR, Northern blot, and a combination of in situ hybridization and immunofluorescence were used to determine the cell-type- and tumor-type-specific MEG3 expression. Bisulfite treatment and PCR sequencing of genomic DNA were used to measure the CpG methylation status in the normal and tumor tissues. Five normal human pituitaries and 17 clinically nonfunctioning, 11 GH-secreting, seven prolactin-secreting, and six ACTH-secreting pituitary adenomas were used. Results: All normal human pituitary cell types express MEG3. However, loss of MEG3 expression occurs only in nonfunctioning pituitary adenomas of a gonadotroph origin. All other pituitary tumor phenotypes examined express MEG3. Hypermethylation of the IG-DMR at the DLK1/MEG3 locus is present in nonfunctioning pituitary adenomas. Conclusions: MEG3 is the first human gene identified expressed in multiple normal human pituitary cell types with loss of expression specifically restricted to clinically nonfunctioning pituitary adenomas. The IG-DMR hypermethylation may be an additional mechanism for MEG3 gene silencing in such tumors.

Pit-1/GHF-1 expression in pituitary adenomas: further analogy between human adenomas and rat SMtTW tumours

1993 ◽  
Vol 11 (2) ◽  
pp. 129-139 ◽  
Author(s):  
M Delhase ◽  
P Vergani ◽  
A Malur ◽  
B Velkeniers ◽  
E Teugels ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pituitary Adenomas ◽  
Anterior Pituitary ◽  
Cell Types ◽  
Cell Type ◽  
Human Pituitary ◽  
Normal Human ◽  
Cell Commitment

ABSTRACT Adenomas can develop from each cell type of the anterior pituitary. In the normal pituitary, three of these cell types, the GH-, prolactin- and TSH-secreting cells, express the transcription factor Pit-1/GHF-1 which is responsible for prolactin and GH (and probably TSH) cell commitment, differentiation, probably proliferation and gene expression. We have analysed the expression of Pit-1/GHF-1 in a panel of human pituitary adenomas. All GH-, prolactin- and TSH-expressing adenomas studied expressed the Pit-1/GHF-1 factor, as demonstrated by in-situ hybridization and immunocytochemistry. The expression was higher in adenomas than in normal human pituitary. In contrast, ACTH- and LH—FSH-secreting and non-secreting adenomas were negative. Seven transplants of the spontaneous rat prolactinoma SMtTW were also investigated and all were found to be positive. This further stresses the analogy between these tumours and human prolactinomas. Taken together, the data confirm that Pit-1/GHF-1 expression is restricted to GH-, prolactin- and TSH-expressing cells, and the increased expression in adenomas is compatible with a role of Pit-1/GHF-1 in cell proliferation.

scholarly journals Thyrotrophin receptor protein expression in normal and adenomatous human pituitary

2000 ◽  
Vol 167 (1) ◽  
pp. 7-13 ◽  
Author(s):  
M Theodoropoulou ◽  
T Arzberger ◽  
Y Gruebler ◽  
Z Korali ◽  
P Mortini ◽  
...  
Keyword(s):  
Protein Expression ◽  
Pituitary Adenomas ◽  
Anterior Pituitary ◽  
Preliminary Evidence ◽  
Positive Control ◽  
Negative Control ◽  
Receptor Protein ◽  
Human Pituitary ◽  
Thyrotrophin Releasing Hormone ◽  
Regulatory Pathways

Thyrotrophin (TSH) synthesis and secretion is under the positive control of thyrotrophin releasing hormone and under the negative control of the thyroid hormones. However, it is hypothesised that TSH has a direct effect on the regulation of its own synthesis through an intrapituitary loop mediated by pituitary TSH receptors (TSH-R). The aim of this investigation was to study the expression of TSH-R in normal human pituitary at mRNA and protein levels, and to compare the pattern of protein expression between different pituitary adenomas. Using RT-PCR we were able to detect TSH-R mRNA in the normal pituitary, and immunohistochemical studies showed TSH-R protein expression in distinct areas of the anterior pituitary. Double immunostaining with antibodies against each of the intrapituitary hormones and S100 revealed that TSH-R protein is present in thyrotrophs and folliculostellate cells. Examination of 58 pituitary adenomas, including two clinically active and two clinically inactive thyrotroph adenomas, revealed TSH-R immunopositivity in only the two clinically inactive thyrotroph adenomas. This study shows, for the first time, the presence of TSH-R protein in the normal anterior pituitary and in a subset of thyrotroph adenomas. The expression of TSH-R in the thyrotroph and folliculostellate cell subpopulations provides preliminary evidence of a role for TSH in autocrine and paracrine regulatory pathways within the anterior pituitary gland.

scholarly journals Differential Regulation of Proopiomelanocortin and Pituitary-Restricted Transcription Factor (TPIT), a New Marker of Normal and Adenomatous Human Corticotrophs

2003 ◽  
Vol 88 (7) ◽  
pp. 3050-3056 ◽  
Author(s):  
Sophie Vallette-Kasic ◽  
Dominique Figarella-Branger ◽  
Michel Grino ◽  
Anne-Marie Pulichino ◽  
Henry Dufour ◽  
...  
Keyword(s):  
Transcription Factor ◽  
In Situ Hybridization ◽  
Pituitary Adenomas ◽  
Experimental Models ◽  
Pituitary Cells ◽  
Human Pituitary ◽  
T Box ◽  
Normal Human ◽  
Human Anterior Pituitary

Since the identification of the pituitary-restricted transcription factor Tpit, a novel T-box factor that is only present in mouse in the two pituitary proopiomelanocortin (POMC)-expressing lineages, no information was available on its pattern of expression in human pituitary. We investigated by immunohistochemistry and in situ hybridization the expression of TPIT in normal human anterior pituitary tissue and in several types of human pituitary adenomas (n = 52). TPIT expression was restricted to the nucleus of normal or adenomatous human corticotroph cells. No specific TPIT immunostaining was detectable in all prolactin (PRL)-, GH-, or gonadotropin-secreting adenomas. In situ hybridization studies demonstrated that TPIT transcripts were coexpressed with POMC mRNA in both secreting and silent corticotroph adenomas, and in normal corticotrophs, whereas TPIT mRNA was not detectable in other types of pituitary adenomas. Unlike POMC, TPIT was not up-regulated by adrenalectomy in rats and did not seem down-regulated in the normal pituitary adjacent to human corticotroph microadenomas. TPIT is the only currently known transcription factor selectively expressed in human normal and adenomatous corticotrophs. In human and experimental models, TPIT and its target gene POMC were thus differentially regulated by glucocorticoids. Moreover, TPIT represents a new marker of POMC-expressing pituitary cells.

Radioimmunoassay detection of endorphins from long-term culture of human pituitary tumour cells

1982 ◽  
Vol 99 (2) ◽  
pp. 174-178 ◽  
Author(s):  
Burt Sharp ◽  
Shlomo Melmed ◽  
Ronald Goldberg ◽  
Harold E. Carlson ◽  
Samuel Refetoff ◽  
...  
Keyword(s):  
Human Serum ◽  
Opioid Peptides ◽  
Anterior Pituitary ◽  
Monolayer Culture ◽  
Pituitary Tumour ◽  
Tumour Cells ◽  
Human Pituitary ◽  
Long Term Culture ◽  
Normal Human

Abstract. Using a sensitive and precise radioimmunoassay for human β-endorphin, we have demonstrated the sustained secretion of opioid peptides from human pituitary tumour cells. Pituitary tumour tissue obtained from a patient with Nelson's syndrome was maintained in continuous monolayer culture and secreted both β-lipotropin and β-endorphin, with predominance of the latter. This is compatible with the idea that the β-endorphin in normal human serum is secreted as such despite the predominance of β-lipotropin compared with β-endorphin in the anterior pituitary.

scholarly journals The Upregulation of Molecules Related to Tumor Immune Escape in Human Pituitary Adenomas

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhiyu Xi ◽  
Pamela S. Jones ◽  
Masaaki Mikamoto ◽  
Xiaobin Jiang ◽  
Alexander T. Faje ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Pituitary Adenomas ◽  
Immune Escape ◽  
Pituitary Tumors ◽  
Human Pituitary ◽  
Tumor Immune Escape ◽  
Human Pituitary Adenomas ◽  
Pituitary Glands ◽  
Normal Human ◽  
Checkpoint Receptors

Human pituitary adenomas are one of the most common intracranial neoplasms. Although most of these tumors are benign and can be treated medically or by transsphenoidal surgery, a subset of these tumors are fast-growing, aggressive, recur, and remain a therapeutic dilemma. Because antibodies against immune checkpoint receptors PD-1 and CLTA-4 are now routinely used for cancer treatment, we quantified the expression of mRNA coding for PD-1, CLTA-4, and their ligands, PD-L1, PD-L2, CD80, and CD86 in human pituitary adenomas and normal pituitary glands, with the ultimate goal of exploiting immune checkpoint therapy in aggressive pituitary adenomas. Aggressive pituitary adenomas demonstrated an increased expression of PD-L2, CD80, and CD86 in compared to that of normal human pituitary glands. Furthermore, aggressive pituitary tumors demonstrated significantly higher levels of CD80 and CD86 compared to non-aggressive tumors. Our results establish a rationale for studying a potential role for immune checkpoint inhibition therapy in the treatment of pituitary adenomas.

scholarly journals Immunohistochemical Localization of Carboxypeptidases D, E, and Z in Pituitary Adenomas and Normal Human Pituitary

2002 ◽  
Vol 50 (11) ◽  
pp. 1509-1515 ◽  
Author(s):  
Xuemo Fan ◽  
Sandy J. Olson ◽  
Lewis S. Blevins ◽  
George S. Allen ◽  
Mahlon D. Johnson
Keyword(s):  
Pituitary Adenomas ◽  
Cell Function ◽  
Expression Patterns ◽  
Immunohistochemical Localization ◽  
Adrenocorticotrophic Hormone ◽  
Null Cell ◽  
Human Pituitary ◽  
Prohormone Processing ◽  
Normal Human ◽  
Carboxypeptidase D

Carboxypeptidases may play important role(s) in prohormone processing in normal and neoplastic adenohypophyseal cells of the pituitary. We have recently demonstrated carboxypeptidase E (CPE) and carboxypeptidase Z (CPZ) in the majority of adenohypophyseal cells with carboxypeptidase D (CPD) immunoreactivity largely confined to adrenocorticotrophs. This study evaluated the expression patterns of CPE, CPD, and CPZ immunoreactivity in 48 pituitary adenomas. Our immunohistochemistry demonstrated extensive intracytoplasmic immunoreactivity for CPE, CPD, and CPZ in adrenocorticotrophic hormone (ACTH)-producing adrenocorticotroph cells, prolactin-producing lactotroph cells, and growth hormone (GH)-producing somatotroph cell adenomas, all of which require carboxypeptide processing of prohormones to produce active endocrine hormones. In contrast to the restricted expression in the normal adenohypophysis, CPD appeared to be widespread in the majority of adenomas, suggesting that CPD levels are increased in adenomas. In luteinizing hormone/follicle-stimulating hormone (LH/FSH)-producing gonadotroph adenomas, which do not require carboxypeptidases to produce gonadotropins, only CPZ immunostaining was demonstrated. In null-cell adenomas, CPE immunoreactivity was detected in the majority of tumors, but CPD and CPZ were identified only in a minority of cases. CPE in these cells may process other peptides critical for pituitary cell function, such as chromogranin A or B. These findings suggest that CPs participate in the functioning of pituitary adenomas.

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