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The prepro-thyrotropin-releasing hormone (ppTRH)-derived peptide, ppTRH178-199, has been proposed to inhibit ACTH release at the level of the pituitary and attenuate prolactin and behavioral responses to stress as well. The objective of this study was to elucidate a possible link between the effects of ppTRH178-199 and glucocorticoids on the inhibition of ACTH release in corticotrophs. Compared with mock-transfected cells, AtT-20 cells that were stably transfected with full-length ppTRH cDNA showed significantly increased sensitivity to dexamethasone, as measured by inhibition of ACTH release. In a group of control cells, expressing a mutated form of ppTRH cDNA lacking the ppTRH178-199 region, sensitivity to dexamethasone was not different from mock-transfected controls. Exogenous ppTRH178-199 also increased the inhibitory effect of dexamethasone in wild-type AtT-20 cells. The combined effect of dexamethasone and ppTRH cDNA in cells that express the latter was not due to increased endogenous secretion of ppTRH178-199 in response to dexamethasone, as dexamethasone was independently found to inhibit secretion of ppTRH178-199. Taken together, these data suggest that ppTRH178-199 can interact with the glucocorticoid negative feedback inhibition to regulate ACTH secretion.
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ABSTRACT
Controversies remain whether atrial natriuretic factor (ANF) may play a role in modulating the release of POMC derived peptides from pituitary corticotrophs. Employing AtT-20 mouse pituitary tumour cells, we report here the effects of rat ANF(1–28) and sodium nitroprusside (SNP), both of which augment cellular levels of cGMP through activating particulate and soluble guanylyl cyclases respectively, on the expression of POMC mRNA abundance. Furthermore, the cellular contents and secretion of (beta endorphin-like immunoreactivity) βEP-LI from these cultures were also examined. Whereas the abundance of POMC mRNA was found to be markedly suppressed following 4h of incubation with rANP(1–28) (0.01 to 1 μM), SNP (0.1 to 10 μM) and dibutyryl-cGMP (1 to 100 μM) in a dose related manner, only a modest reduction in the release and cell contents of βEP-LI was found in some of these cultures. It is also of interest to note that in all the cases examined, the inhibitory effect was associated with a significant suppression of cAMP levels in the cultures. Taken together, our present findings suggest that ANF may play a more important role in suppressing the production than the release of POMC related peptides from AtT-20 cells. Thus, it raises the possibility that hypothalamic ANF may likewise modulate the function of the pituitary-adrenal axis through exerting a greater effect on inhibiting the production than the secretion of pituitary ACTH.
Endocrinology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
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Pituitary Center Rotterdam, Erasmus MC, Rotterdam, The Netherlands
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Department of Internal Medicine and & Medical Specialties (DIMI) and Center of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy
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Pituitary Center Rotterdam, Erasmus MC, Rotterdam, The Netherlands
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(Abcam). The HRP-conjugated anti-β-actin monoclonal antibody was obtained from Santa-Cruz (Santa Cruz Biotechnology). AtT20 cell culture Murine corticotroph AtT20-D16v cells were purchased from ATCC and routinely grown in 75 cm 2 flasks (Corning
Centre for Molecular Endocrinology, William Harvey Research Institute, Barts and The London, Queen Mary’s School of Medicine and Dentistry, University of London, Charterhouse Square, London EC1M 6BQ, UK
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Centre for Molecular Endocrinology, William Harvey Research Institute, Barts and The London, Queen Mary’s School of Medicine and Dentistry, University of London, Charterhouse Square, London EC1M 6BQ, UK
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Centre for Molecular Endocrinology, William Harvey Research Institute, Barts and The London, Queen Mary’s School of Medicine and Dentistry, University of London, Charterhouse Square, London EC1M 6BQ, UK
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Centre for Molecular Endocrinology, William Harvey Research Institute, Barts and The London, Queen Mary’s School of Medicine and Dentistry, University of London, Charterhouse Square, London EC1M 6BQ, UK
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serum (HS; Gibco), 100 U/ml penicillin-G, and 10 mg/ml streptomycin sulfate at 37°C, in a 5% CO 2 –95% air atmosphere. Secretion For secretion studies, AtT20 cells were seeded at 5 × 10 3 cells/well and GH3 cells at 1
Veterinary Basic Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK
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Veterinary Basic Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK
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Veterinary Basic Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK
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Veterinary Basic Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, UK
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-sensitive surrogate insulin-secreting cell by exogenously transfecting the GLP-1 receptor into a transplantable cell line. Previous work has shown that mouse anterior pituitary cells (AtT-20 cells), when transplanted under the adrenal capsule, failed to elicit
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to be the case. Activation of the CaR in murine pituitary corticotroph-derived, AtT-20, cells activated Gα s , increased cAMP production, and stimulated PTHrP and ACTH secretion. Materials and Methods Materials Ham's F12 medium, calcium-free DMEM
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system. More recently, Heaney et al. (2002) reported the effectiveness of thiazolidinedione (TZD), a peroxisome proliferator-activated receptor (PPAR)-γ agonist, on this disorder, again using the AtT20 cell xenograft. Although the precise mechanism of
Gene Therapeutics Research Institute, Cedars-Sinai Medical Center and Department of Medicine and Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, 8700 Beverly Blvd, Davis Building, Suite 5090, Los Angeles, California 90048, USA
Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
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Gene Therapeutics Research Institute, Cedars-Sinai Medical Center and Department of Medicine and Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, 8700 Beverly Blvd, Davis Building, Suite 5090, Los Angeles, California 90048, USA
Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
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Gene Therapeutics Research Institute, Cedars-Sinai Medical Center and Department of Medicine and Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, 8700 Beverly Blvd, Davis Building, Suite 5090, Los Angeles, California 90048, USA
Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
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Gene Therapeutics Research Institute, Cedars-Sinai Medical Center and Department of Medicine and Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, 8700 Beverly Blvd, Davis Building, Suite 5090, Los Angeles, California 90048, USA
Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
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Gene Therapeutics Research Institute, Cedars-Sinai Medical Center and Department of Medicine and Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, 8700 Beverly Blvd, Davis Building, Suite 5090, Los Angeles, California 90048, USA
Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
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Gene Therapeutics Research Institute, Cedars-Sinai Medical Center and Department of Medicine and Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, 8700 Beverly Blvd, Davis Building, Suite 5090, Los Angeles, California 90048, USA
Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
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Gene Therapeutics Research Institute, Cedars-Sinai Medical Center and Department of Medicine and Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, 8700 Beverly Blvd, Davis Building, Suite 5090, Los Angeles, California 90048, USA
Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
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Gene Therapeutics Research Institute, Cedars-Sinai Medical Center and Department of Medicine and Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, 8700 Beverly Blvd, Davis Building, Suite 5090, Los Angeles, California 90048, USA
Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
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Gene Therapeutics Research Institute, Cedars-Sinai Medical Center and Department of Medicine and Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, 8700 Beverly Blvd, Davis Building, Suite 5090, Los Angeles, California 90048, USA
Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
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Gene Therapeutics Research Institute, Cedars-Sinai Medical Center and Department of Medicine and Molecular and Medical Pharmacology, David Geffen School of Medicine, UCLA, 8700 Beverly Blvd, Davis Building, Suite 5090, Los Angeles, California 90048, USA
Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA
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trypan blue exclusion, was over 90%. Cells were cultured in DMEM-S with 10% heat-inactivated fetal bovine serum for 1–2 days (37 °C, 5% CO 2 in air) before RAd virus infection. GH3 and AtT20 cells ( Castro et al. 1997 ) were cultured in MEM
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ABSTRACT
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide originally isolated from ovine hypothalami and so called because of its ability to stimulate pituitary adenylate cyclase activity. Alternative amidation and proteolytic processing of prepro-PACAP gives rise to two bioactive-amidated forms, PACAP-NH2(1–38) (PACAP-38) and PACAP-NH2(1–27) (PACAP-27). 7B2 is a polypeptide of 185 amino acids which is predominantly found in secretory granules and is widely distributed in rat and human tissues. We investigated the ability of the two forms of PACAP to stimulate GH, prolactin and 7B2 release by the rat pituitary clonal cell line GH3, and ACTH and 7B2 by the mouse pituitary clonal cell line AtT-20. PACAP-38 and PACAP-27 stimulated 7B2 and GH/prolactin or ACTH secretion with a similar efficacy over the 2-h incubation period from GH3 and AtT-20 cells respectively. 7B2 secretion was also stimulated by corticotrophin-releasing factor (CRF-41) and vasoactive intestinal polypeptide (VIP) in AtT-20 cells, and thyrotrophin-releasing hormone (TRH) and VIP in GH3 cells. Addition of PACAP to CRF-41 resulted in an additive effect on ACTH secretion and a synergistic effect on 7B2 secretion in AtT-20 cells. No synergism was observed when PACAP was added together with TRH, either on GH and prolactin secretion or on 7B2 release from GH3 cells. PACAP-mediated 7B2 secretion from both cell lines and PACAP-stimulated ACTH release from AtT-20 cells were reduced by 5 mg octapeptide synthetic somatostatin analogue/l (5 mg SMS 201-995/1).
Journal of Endocrinology (1992) 132, 107–113
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Stanniocalcin (STC) is a glycoprotein hormone first discovered in fish as a homeostatic regulator of calcium and phosphate transport; it has recently been discovered in mammals, in which it appears to have a similar role. It has also been implicated in a number of different physiological processes through correlative studies, but the factors regulating its production have not been elucidated. In this report, we show that steady-state STC mRNA levels in the mouse corticotrope tumor line, AtT-20, were exquisitely sensitive to glucocorticoids. Hydrocortisone and dexamethasone (Dex) induced a dramatic reduction in steady-state STC mRNA levels in AtT-20 cells through a post-transcriptional mechanism. Similarly, glucocorticoids down-regulated STC mRNA levels in the human fibrosarcoma cell line, HT1080. The specificity of the glucocorticoid-mediated decrease in STC mRNA abundance was shown using the glucocorticoid receptor antagonist, RU-486. Activation of the cAMP-signaling pathway in glucocorticoid-cultured AtT-20 cells transiently restored STC gene expression. Treatment of AtT-20 cells with the transcriptional inhibitor, actinomycin D, rescued steady-state STC mRNA levels from Dex-induced repression, indicating that the Dex-mediated decrease in STC gene expression requires current gene transcription. Taken together, these results describe a unique model system in which cAMP-stimulated events can reverse post-transcriptional repression of gene expression by glucocorticoids.
