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M. C. Slootweg, R. P. de Groot, M. P. M. Herrmann-Erlee, I. Koornneef, W. Kruijer and Y. M. Kramer

ABSTRACT

Although the structure of several members of the GH receptor family has been defined, signal transduction following GH binding to its receptor has not been elucidated. Mouse osteoblasts were used to study the effect of GH on immediate early gene expression and, subsequently, the cellular signal(s) mediating this expression were analysed. GH rapidly and transiently induced the expression of c-jun and jun B in concert with the already reported expression of c-fos. The GH-induced expression of c-fos was completely blocked by the protein kinase inhibitors staurosporine and H7, indicating that the action of GH is mediated by one or several protein kinases. We next analysed the identity of the putative protein kinases in more detail by using a more specific protein kinase inhibitor, namely the ether-lipid 1-O-alkyl-2-O-methylglycerol, understood to be an inhibitor of protein kinase C (PKC). Data obtained from these studies revealed that GH-induced expression of c-fos is mediated by PKC. In addition, we observed a profound increase in formation of the PKC activator diacyglycerol upon addition of GH, a natural activator of PKC.

In conclusion, upon binding of GH to mouse osteoblasts, the receptor-mediated cellular signal involves diacyglycerol formation and activation of PKC, leading to the induction of oncogene expression. Finally, the expression of c-fos, c-jun and jun B results in an increased binding of protein complexes to AP-1 binding sites.

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Hong Zhou, Yonghua Jiang, Wendy K W Ko, Wensheng Li and Anderson O L Wong

. Furthermore, we also speculate that (i) the JAK2/MAPK cascades secondary coupled to the cAMP-dependent pathway and (ii) the PI3K cascade independent of cAMP-mediated mechanisms may be the key elements in the signal transduction for LH-induced GH gene

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D Roberts and D J Smith

INTRODUCTION

The hormone erythropoietin (EPO), released under hypoxic conditions, acts primarily to stimulate erythrocyte (RBC) production. The association between lack of oxygen, a blood-borne compound, and RBC formation was suggested as early as at the turn of the century (Carnot & DeFlandre, 1906), but it was not until 1957 that the kidneys were identified as the major site of EPO production in the adult mammal (Jacobson et al. 1957). The first purification of EPO was from plasma of anaemic sheep in 1971 (Goldwasser & Kung, 1971). Despite an extensive procedure, the yield and specific activity of the product were extremely low (0·4% and 8250 U/mg protein respectively). In 1977, the same procedure was used with 2550 litres of urine from anaemic humans, generating a product with a specific activity of 74 000 U/mg protein (Miyake et al. 1977). Characterization of the hormone was hampered by the difficulty of obtaining a

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Michelle Mohyi and Terry J Smith

uncharacterized; however, key insights have begun to emerge. Signal transduction pathways used by the two receptors overlap ( Dupont & LeRoith 2001 , Latif et al . 2009 , Morshed et al . 2009 , 2010 ), suggesting the potential for functional interplay between

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Pál Gyombolai, András D Tóth, Dániel Tímár, Gábor Turu and László Hunyady

– 197 . ( doi:10.1146/annurev.pharmtox.010909.105800 ). Rhee MH Nevo I Levy R Vogel Z 2000 Role of the highly conserved Asp-Arg-Tyr motif in signal transduction of the CB2 cannabinoid receptor . FEBS Letters 466 300 – 304 . ( doi:10

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Michael Welsh, Maria Jamalpour, Guangxiang Zang and Björn Åkerblom

Lindholm CK Kriz V Welsh M 2003 The FRK/RAK-SHB signaling cascade: a versatile signal-transduction pathway that regulates cell survival, differentiation and proliferation . Current Molecular Medicine 3 313 – 324 . ( doi:10

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V. C. Parrow, J. O. Gordeladze, E. J. Paulssen, P. Aleström and K. M. Gautvik

ABSTRACT

In GH12C1 rat pituitary cells treated with 5-azacytidine, the stimulatory effects exerted by vasoactive intestinal peptide (VIP), the GTP analogue guanyl-5′-yl imidodiphosphate (Gpp(NH)p), 12-O-tetradecanoyl phorbol 13-acetate, cholera toxin and pertussis toxin on the membrane-bound adenylyl cyclase were almost completely abolished. The corresponding inhibitory effect of somatostatin was increased. Alterations in adenylyl cyclase responsiveness began at the end of the drug treatment, and were most pronounced on day 5 after removal of 5-azacytidine. The cells subsequently and completely recovered after 10 days in the absence of the drug. Measurements of cholera toxin- and VIP-enhanced cyclic AMP levels in intact cells confirmed these results, and VIP appeared to have no stimulatory effect on GH secretion after 5-azacytidine treatment. Down-regulation of Gαs RNA also occurred on day 5 after cessation of drug treatment. ADP-ribosylation subsequent to stimulation with pertussis toxin was markedly increased, indicating an enhancement of Gαi and/or GGαo. Furthermore, both basal and Gpp(NH)p-stimulated phospholipase C activities were augmented by pre-exposure to 5-azacytidine.

Treatment of GH12C1 rat pituitary tumour cells with 5-azacytidine therefore causes a marked but temporary increase in the ratio of Gαi/Gαs protein levels.

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Heather E Bergan, Jeffrey D Kittilson and Mark A Sheridan

et al . 2005 ). Despite extensive knowledge of GH signal transduction ( Waters et al . 2006 ), the mechanism(s) by which GH enhances lipolysis as well as how these mechanisms integrate with other actions of GH (e.g. growth, reproduction, and

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Fumihiko Hakuno and Shin-Ichiro Takahashi

R69 – R75 . ( https://doi.org/10.1172/JCI8339 ) 10.1172/JCI8339) Kurihara S Hakuno F Takahashi S 2000 Insulin-like growth factor-I-dependent signal transduction pathways leading to the induction of cell growth and differentiation of human

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B Gallwitz, M Witt, U R Fölsch, W Creutzfeldt and W E Schmidt

ABSTRACT

Glucagon-like peptide-1(7–36)amide (GLP-1(7–36) amide) and gastric inhibitory polypeptide (GIP), peptides of the glucagon family, stimulate insulin secretion in vitro and in vivo. They possess high N-terminal sequence homology. Binding studies with 125I-labelled GIP and 125I-labelled GLP-1(7– 36)amide were performed in RINm5F insulinoma cells to investigate receptor specificity and to compare both receptors directly. Both binding sites were highly ligand-specific: GIP did not bind to the GLP-1(7–36)amide receptor and vice versa. Both peptides increased intracellular cyclic AMP levels; GLP-1(7– 36)amide was 100-fold more potent in stimulating cyclic AMP production when compared with GIP. At ranges of 1–10 nmol GLP-1(7–36)amide/1 and 0·1–10 GIP/1, corresponding to submaximal binding concentrations, the hormones showed an additive effect on cyclic AMP production. The N-terminal portion of GIP was important for binding, as GIP(1–30) showed almost full binding and biological activity. GIP(17–42) bound in a concentration-dependent manner with approximately 500-fold lower potency than GIP. At concentrations of up to 10 μmol GIP(17–42)/1 no stimulation of cyclic AMP was observed.