scholarly journals Downregulation of the GHRH/GH/IGF1 axis in a mouse model of Börjeson-Forssman-Lehman syndrome

Development ◽  
2020 ◽  
Vol 147 (21) ◽  
pp. dev187021
Author(s):  
Helen M. McRae ◽  
Samantha Eccles ◽  
Lachlan Whitehead ◽  
Warren S. Alexander ◽  
Jozef Gécz ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Body Size ◽  
Mouse Model ◽  
Negative Regulator ◽  
Growth Defect ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Plant Homeodomain Finger ◽  
Genes Encoding ◽  
Proportional Reduction

ABSTRACTBörjeson-Forssman-Lehmann syndrome (BFLS) is an intellectual disability and endocrine disorder caused by plant homeodomain finger 6 (PHF6) mutations. Individuals with BFLS present with short stature. We report a mouse model of BFLS, in which deletion of Phf6 causes a proportional reduction in body size compared with control mice. Growth hormone (GH) levels were reduced in the absence of PHF6. Phf6−/Y animals displayed a reduction in the expression of the genes encoding GH-releasing hormone (GHRH) in the brain, GH in the pituitary gland and insulin-like growth factor 1 (IGF1) in the liver. Phf6 deletion specifically in the nervous system caused a proportional growth defect, indicating a neuroendocrine contribution to the phenotype. Loss of suppressor of cytokine signaling 2 (SOCS2), a negative regulator of growth hormone signaling partially rescued body size, supporting a reversible deficiency in GH signaling. These results demonstrate that PHF6 regulates the GHRH/GH/IGF1 axis.

scholarly journals Regulation and role of suppressor of cytokine signaling-3 in hypothalamic 4B cells

2009 ◽  
Vol 201 (3) ◽  
pp. 369-376 ◽  
Author(s):  
Kazunori Kageyama ◽  
Komaki Hanada ◽  
Yasumasa Iwasaki ◽  
Toshihiro Suda
Keyword(s):  
Gene Expression ◽  
Stress Responses ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Mrna Levels ◽  
Suppressor Of Cytokine Signaling ◽  
Hypothalamic Cells ◽  
Parvocellular Neurons ◽  
Response To Stress ◽  
Inhibitory Signaling

Corticotropin-releasing factor (CRF) plays a central role in regulating stress responses. In the hypothalamic paraventricular nucleus (PVN), CRF, produced in response to stress, stimulates the release of ACTH from the anterior pituitary. ACTH then stimulates the release of glucocorticoids from the adrenal glands; circulating glucocorticoids are critical for recovery from stress conditions. Cytokines are also implicated in the regulation of CRF expression. Among them, interleukin (IL)-6 plays a role in the regulation of CRF. Factors other than glucocorticoids are likely to be involved in limiting the stimulation of CRF during stress. Suppressor of cytokine signaling (SOCS)-3 acts as a potent negative regulator of cytokine signaling. Little is known about the ability of the inhibitory signaling pathways to limit activation of the CRF gene in parvocellular PVN neurons. Hypothalamic 4B cells are useful for exploring the mechanisms, because these cells show characteristics of the parvocellular neurons of the PVN. In the present study, we examined whether SOCS-3 is regulated by IL-6 and cAMP in hypothalamic 4B cells. We also explored the involvement of SOCS-3 in the regulation of CRF gene expression. SOCS-3 was found to be regulated by IL-6 and via the cAMP/protein kinase A pathway in the hypothalamic cells. SOCS-3 knockdown increased IL-6- or forskolin-induced CRF gene transcription and mRNA levels. Therefore, SOCS-3, induced by a cAMP stimulant and IL-6, would be involved in the negative regulation of CRF gene expression in hypothalamic cells.

The myeloproliferative disorder–associated JAK2 V617F mutant escapes negative regulation by suppressor of cytokine signaling 3

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4924-4929 ◽  
Author(s):  
Michelle B. Hookham ◽  
Joanne Elliott ◽  
Yvonne Suessmuth ◽  
Judith Staerk ◽  
Alister C. Ward ◽  
...  
Keyword(s):  
Tyrosine Phosphorylation ◽  
Mononuclear Cells ◽  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Peripheral Blood Mononuclear ◽  
Socs3 Protein ◽  
Mutant Kinase

Abstract The somatic JAK2 valine-to-phenylalanine (V617F) mutation has been detected in up to 90% of patients with polycythemia and in a sizeable proportion of patients with other myeloproliferative disorders such as essential thrombocythemia and idiopathic myelofibrosis. Suppressor of cytokine signaling 3 (SOCS3) is known to be a strong negative regulator of erythropoietin (EPO) signaling through interaction with both the EPO receptor (EPOR) and JAK2. We report here that JAK2 V617F cannot be regulated and that its activation is actually potentiated in the presence of SOCS3. Instead of acting as a suppressor, SOCS3 enhanced the proliferation of cells expressing both JAK2 V617F and EPOR. Additionally, although SOCS1 and SOCS2 are degraded in the presence of JAK2 V617F, turnover of SOCS3 is inhibited by the JAK2 mutant kinase and this correlated with marked tyrosine phosphorylation of SOCS3 protein. We also observed constitutive tyrosine phosphorylation of SOCS3 in peripheral blood mononuclear cells (PBMCs) derived from patients homozygous for the JAK2 V617F mutant. These findings suggest that the JAK2 V617F has overcome normal SOCS regulation by hyperphosphorylating SOCS3, rendering it unable to inhibit the mutant kinase. Thus, JAK2 V617F may even exploit SOCS3 to potentiate its myeloproliferative capacity.

scholarly journals CXCR4-mediated Suppressor of Cytokine Signaling Up-regulation Inactivates Growth Hormone Function

2004 ◽  
Vol 279 (43) ◽  
pp. 44460-44466 ◽  
Author(s):  
Ruth Garzón ◽  
Silvia F. Soriano ◽  
José Miguel Rodríguez-Frade ◽  
Lucio Gómez ◽  
Ana Martín de Ana ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Cytokine Signaling ◽  
Suppressor Of Cytokine Signaling

scholarly journals Liver X receptor agonist downregulates growth hormone signaling in the liver

2011 ◽  
Vol 8 (2) ◽  
Author(s):  
Fahad Zadjali ◽  
Ruyman Santana-Farre ◽  
Mercedes Mirecki-Garrido ◽  
Ewa Ellis ◽  
Gunnar Norstedt ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Hepatic Steatosis ◽  
Hepatic Metabolism ◽  
Liver X Receptor ◽  
Cytokine Signaling ◽  
Hormone Signaling ◽  
Suppressor Of Cytokine Signaling ◽  
Lxr Agonists ◽  
Liver X Receptor Agonist ◽  
Gh Receptors

AbstractLiver X receptor (LXR) agonists have been shown to influence the development of hyperlipidemia and atherosclerosis in mouse models. It has also been demonstrated that some LXR agonists can cause hepatic steatosis in experimental animals. Growth hormone (GH) is known to regulate hepatic metabolism and the absence of hepatic GH receptors (GHR) leads to hepatic steatosis. In this study, we analyzed whether the actions of LXR agonists could involve interference with GH signaling. We showed that LXR agonists impair GH signaling in hepatocytes. LXR agonist treatment attenuated GH induction of suppressor of cytokine signaling 2 (

scholarly journals The role of suppressor of cytokine signaling 1 as a negative regulator for aberrant expansion of CD8α+ dendritic cell subset

2005 ◽  
Vol 17 (9) ◽  
pp. 1167-1178 ◽  
Author(s):  
Jun Tsukada ◽  
Akemi Ozaki ◽  
Toshikatsu Hanada ◽  
Takatoshi Chinen ◽  
Ryo Abe ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Cell Subset ◽  
Negative Regulator ◽  
Cytokine Signaling ◽  
Dendritic Cell Subset ◽  
Suppressor Of Cytokine Signaling

scholarly journals Altered Growth in Male Peroxisome Proliferator-Activated Receptor γ (PPARγ) Heterozygous Mice: Involvement of PPARγ in a Negative Feedback Regulation of Growth Hormone Action

2004 ◽  
Vol 18 (10) ◽  
pp. 2363-2377 ◽  
Author(s):  
Jennifer Rieusset ◽  
Josiane Seydoux ◽  
Silvia I. Anghel ◽  
Pascal Escher ◽  
Liliane Michalik ◽  
...  
Keyword(s):  
Body Size ◽  
Negative Regulator ◽  
Mutant Mice ◽  
Cytokine Signaling ◽  
Peroxisome Proliferator ◽  
Gene Encoding ◽  
Negative Feedback Regulation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Reduced Body ◽  
Igf I

Abstract The peroxisome proliferator-activated receptor γ (PPARγ) plays a major role in fat tissue development and physiology. Mutations in the gene encoding this receptor have been associated to disorders in lipid metabolism. A thorough investigation of mice in which one PPARγ allele has been mutated reveals that male PPARγ heterozygous (PPARγ +/−) mice exhibit a reduced body size associated with decreased body weight, reflecting lean mass reduction. This phenotype is reproduced when treating the mice with a PPARγ- specific antagonist. Monosodium glutamate treatment, which induces weight gain and alters body growth in wild-type mice, further aggravates the growth defect of PPARγ +/− mice. The levels of circulating GH and that of its downstream effector, IGF-I, are not altered in mutant mice. However, the IGF-I mRNA level is decreased in white adipose tissue (WAT) of PPARγ +/− mice and is not changed by acute administration of recombinant human GH, suggesting an altered GH action in the mutant animals. Importantly, expression of the gene encoding the suppressor of cytokine signaling-2, which is an essential negative regulator of GH signaling, is strongly increased in the WAT of PPARγ +/− mice. Although the relationship between the altered GH signaling in WAT and reduced body size remains unclear, our results suggest a novel role of PPARγ in GH signaling, which might contribute to the metabolic disorder affecting insulin signaling in PPARγ mutant mice.

Sign in / Sign up

Export Citation Format

Share Document