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      Natriuretic Peptide Receptors of Type A in Human Neuroblastomas

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          Functional natriuretic peptide receptors of type A (NPR-A) were detected in the human neuroblastoma NB-OK-1, SK-N-SH and SK-N-BE, but not the SH-SY5Y, cell lines. Also, NPR-A mRNA was detected in 19 of the 25 tumor neuroblastoma samples tested in this study. Five of the eight tumor neuroblastoma samples that were assayed for atrial natriuretic peptide (ANP) binding revealed the presence of ANP-binding sites. In the human neuroblastoma NB-OK-1 cell line, [<sup>3</sup>H] thymidine incorporation was increased in response to ANP, decreased in response to pituitary adenylate cyclase-activating polypeptide (PACAP-27), and the stimulatory effect of ANP was inhibited by PACAP-27. Tissue transglutaminase activity was decreased by ANP and PACAP-27, and their effects were additive. However, neither cell cycle phases, cell growth, or cell apoptosis were modified by ANP or PACAP-27 treatments.

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          Most cited references 5

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          Modulation of the in situ activity of tissue transglutaminase by calcium and GTP.

          Tissue transglutaminase (tTG) is a calcium-dependent enzyme that catalyzes the posttranslational modification of proteins by transamidation of specific polypeptide-bound glutamine residues. Previous in vitro studies have demonstrated that the transamidating activity of tTG requires calcium and is inhibited by GTP. To investigate the endogenous regulation of tTG, a quantitative in situ transglutaminase (TG) activity assay was developed. Treatment of human neuroblastoma SH-SY5Y cells with retinoic acid (RA) resulted in a significant increase in tTG levels and in vitro TG activity. In contrast, basal in situ TG activity did not increase concurrently with RA-induced increased tTG levels. However, stimulation of cells with the calcium-mobilizing drug maitotoxin (MTX) resulted in increases in in situ TG activity that correlated (r2 = 0.76) with increased tTG levels. To examine the effects of GTP on in situ TG activity, tiazofurin, a drug that selectively decreases GTP levels, was used. Depletion of GTP resulted in a significant increase in in situ TG activity; however, treatment of SH-SY5Y cells with a combination of MTX and tiazofurin resulted in significantly less in situ TG activity compared with treatment with MTX alone. This raised the possibility of calcium-dependent proteolysis due to the effects of tiazofurin, because in vitro GTP protects tTG against proteolysis by trypsin. Studies with a selective membrane permeable calpain inhibitor indicated that tTG is likely to be an endogenous substrate of calpain, and that depletion of GTP increases tTG degradation after elevation of intracellular calcium levels. TG activity was also increased in response to activation of muscarinic cholinergic receptors, which increases intracellular calcium through inositol 1,4,5-trisphosphate generation. The results of these experiments demonstrate that selective changes in calcium and GTP regulate the activity and levels of tTG in situ.
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            Atrial natriuretic peptide induces apoptosis in neonatal rat cardiac myocytes.

            Early heart failure is characterized by elevated plasma atrial natriuretic peptide (ANP) levels, but little is known about the direct effects of ANP on cardiac myocytes. In neonatal rat cardiac myocytes, ANP induced apoptosis in a dose-dependent and cell type-specific manner. Maximum effects occurred at 1 microM ANP, with a 4-5-fold increase in apoptotic cells, reaching a maximum apoptotic index of 19%. In contrast, the maximum apoptotic index of ANP-treated non-myocytes was 1.1 +/- 0.2%, equivalent to control cultures. ANP treatment also sharply reduced levels of Mcl-1 mRNA, a Bcl-2 homologue, coincident with the increase in the incidence of apoptosis. ANP induction of apoptosis was receptor-dependent and mediated by cyclic GMP: the effect was mimicked by 8-bromo-cGMP, a membrane-permeable analog, and by sodium nitroprusside, an activator of soluble guanylyl cyclase, and was potentiated by a cGMP-specific phosphodiesterase inhibitor, zaprinast. Interestingly, norepinephrine, a myocyte growth factor, inhibited ANP-induced apoptosis via activation of the beta-adrenergic receptor and elevation of cyclic AMP. These results show that ANP is a specific effector of cardiac myocyte apoptosis in culture via receptor-mediated elevation of cGMP. Furthermore, at least in this model, ANP and norepinephrine may have opposing roles in the modulation of cardiac myocyte growth and survival.
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              Pituitary adenylate cyclase activating peptide and its receptors are expressed in human neuroblastomas.

              Vasoactive intestinal peptide (VIP) has been considered as an autocrine growth factor in neuroblastomas. Pituitary adenylate cyclase activating polypeptides (PACAPs) are newly recognized members of the VIP family of neurohormones. As compared to VIP, PACAP has been reported to be biologically more potent and more efficient in tissues expressing selective PACAP receptors rather than common VIP/PACAP receptors. PACAPs and VIP interact with the same affinity and stimulate adenylate cyclase activity with the same efficacy and potency on the VIP receptors, but PACAPs act also on a more selective PACAP receptor that also recognizes VIP but with a 100- to 1,000-fold lower affinity. Thus, depending on the type of receptors expressed at a cell surface, PACAP may be more potent and efficient than VIP. The capacity of 22 surgical specimens of neuroblastomas and of 5 established cell lines to synthesize PACAP and VIP and to synthesize and express PACAP receptors and VIP receptors was studied. Using the reverse transcriptase-polymerase chain (RT-PCR) method with specific primers, we detected the mRNAs coding for PACAP and VIP in 19 and 3 out of 22 samples, respectively. PACAP mRNA was expressed in 3 of the 5 cell lines studied and VIP mRNA in 4. Using the same techniques, PACAP and VIP receptors mRNA were detected in 21, and 13 of the 22 tumor samples and in 5 and 1 of the cell lines studied, respectively. The expression of the PACAP receptor was demonstrated by direct binding studies and/or by the relative potency of PACAPs and VIP to stimulate adenylate cyclase activity in 16 of the 22 tumors and in all the cell lines. In addition, there was no correlation between tumor stage and the expression of mRNA coding for the peptides and the receptors. The present results demonstrated that PACAP could also be a candidate as an autocrine regulator of neuroblastoma which a higher activity than VIP.

                Author and article information

                S. Karger AG
                October 1999
                14 October 1999
                : 70
                : 4
                : 288-294
                aDepartment of Biochemistry and Nutrition and bDepartment of Immunology, Medical School, Université Libre de Bruxelles, Brussels, Belgium
                54488 Neuroendocrinology 1999;70:288–294
                © 1999 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 3, References: 28, Pages: 7
                Clinical Neuroendocrinology


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