Regulation of growth-hormone-receptor gene expression by growth hormone and pegvisomant in human mesangial cells

Regulation of growth-hormone-receptor gene expression by growth hormone and pegvisomant in human mesangial cells.BackgroundMice transgenic for growth hormone develop mesangial proliferation, glomerular hypertrophy, and progressive glomerular sclerosis suggesting that the growth hormone–insulin-like growth factor I (IGF-I) pathway plays an important role. Therefore, we studied the impact of variable concentrations of 22 kD, 20 kD growth hormone, as well as of the growth hormone receptor antagonist pegvisomant (B2036-PEG), on both the growth hormone receptor (GHR/GHBP) gene expression and growth hormone binding protein (GHBP) formation in a human glomerular mesangial cell line. Further, the impact on collagen, IGF-I and IGF binding protein-1 (IGFBP-1) formation was studied.MethodsIn order to assess transcription, quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used.ResultsPhysiologic doses of 22 kD or 20 kD growth hormone caused a dose-dependent and significant (P < 0.01) up-regulation of GHR/GHBP gene transcription, whereas supraphysiologic doses (50 and 500ng/mL) resulted in down-regulation (P < 0.001). Whenever pegvisomant was used, there was no increase in GHR/GHBP expression. These data were confirmed using run-on experiments. Further, the assessment of GHBP presented a constant, dose-dependent increase, which was completely abolished in the experiments where pegvisomant was used.ConclusionWe present data showing that growth hormone has a direct impact on GHR/GHPB gene transcription and that pegvisomant is a potent growth hormone receptor antagonist in human mesangial cells. In addition, although the GHR/GHBP gene transcription is down-regulated by supraphysiologic growth hormone concentrations, this effect was not found when GHBP levels were measured. This finding may reflect a self-inhibitory effect of growth hormone on the level of GHR/GHBP gene transcription, which does not involve the regulation of the shedding of GHBP and may, therefore, be of physiologic interest

Intrusive digital advertising : from control to resistance ?

National audienceMobile digital advertising is now accounting for half of advertising investments. However ad intrusiveness seems to induce resistance behaviors from users. Our research analyzes the relationships between intrusion, perceived control and resistance in a context of exposure to display mobile advertising. A qualitative study confirms the multi-dimensionality of the perceived control concept as well as the occurrence of resistance behaviors due to a user lack of control. The reinforcement of the Internet users' data protection by public authorities makes it necessary to deepen the work on understanding the role of control in the users' acceptance of display mobile ads

GH mutant (R77C) in a pedigree presenting with the delay of growth and pubertal development: structural analysis of the mutant and evaluation of the biological activity

A heterozygous missense mutation in the GH-1 gene converting codon 77 from arginine (R) to cysteine (C), which was previously reported to have some GH antagonistic effect, was identified in a Syrian family. The index patient, a boy, was referred for assessment of his short stature (-2.5 SDS) at the age of 6 years. His mother and grandfather were also carrying the same mutation, but did not differ in adult height from the other unaffected family members. Hormonal examination in all affected subjects revealed increased basal GH, low IGF-I concentrations, and subnormal IGF-I response in generation test leading to the diagnosis of partial GH insensitivity. However, GH receptor gene (GHR) sequencing demonstrated no abnormalities. As other family members carrying the GH-R77C form showed similar alterations at the hormonal level, but presented with normal final height, no GH therapy was given to the boy, but he was followed through his pubertal development which was delayed. At the age of 20 years he reached his final height, which was normal within his parental target height. Functional characterization of the GH-R77C, assessed through activation of Jak2/Stat5 pathway, revealed no differences in the bioactivity between wild-type-GH (wt-GH) and GH-R77C. Detailed structural analysis indicated that the structure of GH-R77C, in terms of disulfide bond formation, is almost identical to that of the wt-GH despite the introduced mutation (Cys77). Previous studies from our group demonstrated a reduced capability of GH-R77C to induce GHR/GH-binding protein (GHBP) gene transcription rate when compared with wt-GH. Therefore, reduced GHR/GHBP expression might well be the possible cause for the partial GH insensitivity found in our patients. In addition, this group of patients deserve further attention because they could represent a distinct clinical entity underlining that an altered GH peptide may also have a direct impact on GHR/GHBP gene expression causing partial GH insensitivity. This might be responsible for the delay of growth and pubertal development. Finally, we clearly demonstrate that GH-R77C is not invariably associated with short stature, but that great care needs to be taken in ascribing growth failure to various heterozygous mutations affecting the GH-IGF axis and that careful functional studies are mandatory

Synthesis and antitumoral activity of novel thiazolobenzotriazole, thiazoloindolo[3,2-c]quinoline and quinolinoquinoline derivatives

International audienc

Short stature caused by a biologically inactive mutant growth hormone (GH-C53S).

Human GH has two disulfide bridges linking Cys-53 to Cys-165 and Cys-182 to Cys-189. Although absence of the first disulfide bridge has been shown to affect the bioactivity of GH in transgenic mice, little is known of the importance of this bridge in mediating the GH/GH-receptor (GHR) interaction in humans. However, we have identified a missense mutation (G705C) in the GH1 gene of a Serbian patient. This mutation was found in the homozygous state and leads to the absence of the disulfide bridge Cys-53 to Cys-165. To study the impact of this mutation in vitro, GHR binding and Janus kinase (Jak)2/signal transducer and activator of transcription (Stat)5 activation experiments were performed, in which it was observed that at physiological concentrations (3-50 ng/ml) both GHR binding and Jak2/Stat5 signaling pathway activation were significantly reduced in the mutant GH-C53S, compared with wild-type (wt)-GH. Higher concentrations (400 ng/ml) were required for this mutant to elicit responses similar to wt-GH. These results demonstrate that the absence of the disulfide bridge Cys-53 to Cys-165 affects the binding affinity of GH for the GHR and subsequently the potency of GH to activate the Jak2/Stat5 signaling pathway. In conclusion, we have demonstrated that GH-C53S is a bioinactive GH at the physiological range and that the disulfide bridge Cys-53 to Cys-163 is required for mediating the biological effects of GH

Ré-écrire l’Écosse : histoire

Ce numéro de la revue Études écossaises poursuit le travail d'exploration entamé dans le volume précédent (n° 15) pour se consacrer, après la littérature et au cinéma, à la thématique de la réécriture de l’histoire. Le Centre d’études sur les modes de la représentation anglophone (CEMRA), auquel est rattachée notre revue, travaille actuellement sur les phénomènes de révisions, transmutations et translations et, notamment, sur les mécanismes de réappropriation, réévaluation et contestation de discours et courants de pensée dominants. L’histoire écossaise et les enjeux sur lesquels a souvent reposé son écriture se sont tout naturellement imposés comme susceptibles de fournir, à cet égard, de nombreux exemples de dynamiques ayant pu affecter — ou affectant encore — des interprétations jugées canoniques de la société et de la politique. Les travaux présentés revêtent d’une importance accrue à un moment historique où les Écossais se préparent à se prononcer sur le rôle constitutionnel de l’Écosse au sein de l’Union britannique

Ré-écrire l’Écosse : histoire

Ce numéro de la revue Études écossaises poursuit le travail d'exploration entamé dans le volume précédent (n° 15) pour se consacrer, après la littérature et au cinéma, à la thématique de la réécriture de l’histoire. Le Centre d’études sur les modes de la représentation anglophone (CEMRA), auquel est rattachée notre revue, travaille actuellement sur les phénomènes de révisions, transmutations et translations et, notamment, sur les mécanismes de réappropriation, réévaluation et contestation de discours et courants de pensée dominants. L’histoire écossaise et les enjeux sur lesquels a souvent reposé son écriture se sont tout naturellement imposés comme susceptibles de fournir, à cet égard, de nombreux exemples de dynamiques ayant pu affecter — ou affectant encore — des interprétations jugées canoniques de la société et de la politique. Les travaux présentés revêtent d’une importance accrue à un moment historique où les Écossais se préparent à se prononcer sur le rôle constitutionnel de l’Écosse au sein de l’Union britannique

Endoplasmic reticulum stress controls iron metabolism through TMPRSS6 repression and hepcidin mRNA stabilization by RNA-binding protein HuR

International audienceThe liver hormone hepcidin controls the main inflowsof iron into plasma by binding to and inducing the degra-dation or the occlusion of the iron export activity of fer-roportin, the only known cellular exporter of iron.1,2When hepcidin concentrations are high, iron is trapped inenterocytes of the duodenum, hepatocytes, andmacrophages. Hepcidin production by the hepatocytes isinduced by a number of stimuli, most notably iron,through the BMP-SMAD signaling pathway,3 and inflam-matory signals, through the IL-6/ STAT3 signaling axis.4In addition, hepcidin has also been reported to respondto intracellular stress, namely endoplasmic reticulum (ER)stress which is involved in a number of pathophysiologi-cal states, including the inflammatory response, nutrientdisorders and viral infection. A previous study has sug-gested that hepcidin induction by ER stress is controlledby the BMP-SMAD pathway,5 but the exact mechanismis still uncertai