Searchable abstracts of presentations at key conferences in endocrinology

ea0004s22 | Journal of Endocrinology Symposium: Young Innovations - Society for Endocrinology Research Fellows Update | SFE2002

TRUNCATED CYTOKINE RECEPTORS AND GH ANTAGONISTS: SIGNALLING AND TRAFFICKING

Maamra M

Common features for cytokine receptors are the presence of truncated receptors and production of soluble receptor. mRNAs encoding truncated growth hormone and leptin receptors (GHR and ObR) have been detected. The truncated GHR1-279 has a dominant negative action on the full-length receptor (GHRfl). GH is internalised very rapidly by cells expressing GHRfl. In contrast, the GHR1-279 showed delayed and reduced internalisation of GH. This could explain its dominant negative acti...

ea0009p36 | Growth and development | BES2005

SOCS proteins inhibit leptin signalling in MCF-7 cells

Fazeli M , Maamra M , Ross R

Introduction: Leptin is a pro-inflammatory cytokine and excess leptin in obesity may induce autoimmune disease. The suppressors of cytokine signalling (SOCS) are negative regulators of cytokine signalling and therefore a target for therapy. SOCS3 modulates leptin actions but there is no data regarding other SOCS proteins and leptin signalling.Aim: To develop a bioassay and examine the actions of SOCS proteins on leptin signalling.M...

ea0002sp19 | <emphasis>Journal of Molecular Endocrinology</emphasis> Symposium: Receptor Antagonists | SFE2001

Growth Hormone Antagonists

Ross R , Justice S , Maamra M

The development of the growth hormone antagonist, Pegvisomant, is a story of modern drug design. The original observation was by John Kopchick, who noted that transgenic mice with a mutation in the third alpha helix of the GH molecule had a dwarf phenotype. This is the basis for the site 2 mutation (G120K) in the GH molecule that blocks GH signaling. At the same time the Genetech group of James Wells had characterised the crystal structure of the GH/receptor complex demonstrat...

ea0007oc15 | Development and growth | BES2004

Internalization of the GH antagonist pegvisomant

Maamra M , Kopchick J , Strasburger C , Ross R

Pegvisomant is a specific GH antagonist developed for the treatment of acromegaly. Pegvisomant is a GH antagonist molecule with an amino acid substitution that blocks the conformational change necessary for signal transduction and polyethylene glycol (PEG) moieties to improve clinical efficacy. Pegvisomant has a long plasma half-life and its mode of clearance has not been established. We hypothesised that GHR mediated internalisation of Pegvisomant might be one mechanism for i...

ea0007p23 | Cytokines and growth factors | BES2004

Effects of estrogen on leptin signalling and leptin-induced TNF-alpha production

Fazeli M , Zarkesh-Esfahani S , Maamra M , Ross R

Introduction: Leptin modulates immune activation in relation to nutritional state and there is gender difference in body composition and the immune response. Leptin induces the release of pro-inflammatory cytokines, including TNF-alpha, from human peripheral blood mononuclear cells (PBMCs). We hypothesised that estrogen may modulate the immune actions of leptin. Aim: To test the effect of estrogen on leptin signalling and leptin-induced TNF-alpha production. Materials and Meth...

ea0011p246 | Cytokines and growth factors | ECE2006

GH and GH antagonist B2036 effect on the immune system

Maamra M , Perna F , Colao A , Pivonello R , Zappacosta S , Ross RJM , Matarese G

Introduction: Growth Hormone (GH) receptors are expressed on, and GH is secreted by, human peripheral blood mononuclear cells (PBMCs). However, the role of GH in immunity has remained elusive and studies have given conflicting results. Experimental data strongly implicates a role for pituitary GH in the immune response of rodents. The data from knockout mice suggests that GH acts not as an obligate immunoregulator but as an anabolic and stress-modulating hormone. Despite the c...

ea0005p76 | Cytokines and Growth Factors | BES2003

Development of a bioassay for leptin agonists and antagonists

Fazeli M , Zarkesh-Esfahani H , Maamra M , Justice S , Ross R

Introduction: Identifying leptin agonists and antagonists requires a reliable bioassay responsive to physiological levels of leptin. The leptin receptor exists in multiple isoforms but Ob-Rb, the full length receptor, mediates the biological actions of leptin and its predominant signalling pathway is through STAT3. We report the development of a bioassay based on a STAT3 firefly luciferase reporter. Materials and Methods: HEK 293 cells were transfected with varying amounts of ...

ea0003oc32 | Metabolism | BES2002

Regulation of leptin receptor cleavage

Maamra M , Bidlingmaier M , Postel-Vinay M , Wu Z , Strasburger C , Ross R

The leptin receptor (ObR) exists in multiple isoforms. In humans, there is no mRNA encoding soluble receptor (LBP). We investigated the hypothesis that human LBP can be generated by proteolytic cleavage of membrane anchored leptin receptors (ObRb and ObRa). LBP, of similar size to that previously detected in human serum, was detected in medium of cells transfected with ObRa by HPLC, Immunofluorometric assay, and Ligand mediated immunofluorometric assay, but not by ELISA. The L...

ea0005p70 | Cytokines and Growth Factors | BES2003

Growth hormone (GH) insensitivity due to a mutation in the cytoplasmic domain of the GH receptor distal to Box 1

Milward A , Metherell L , Maamra M , Wilkinson I , Camacho-Hubner C , Savage M , Ross R , Clark A , Webb S

Background: The majority of patients with GH insensitivity have defects in the extracellular domain of the GHR. We have identified a 47yr old woman homozygous for a 22bp deletion in the cytoplasmic domain of the GHR. The patient had high GH levels, and low IGF-1 of 8 ug/L (normal 54-389 ug/L), IGFBP-3 16nmol/L (normal 61-254 nmol/L) and GHBP 6.8 percent (normal greater than 10 percent) levels. We report functional studies for this mutation (GHR1-449) which results in premature...

ea0005p71 | Cytokines and Growth Factors | BES2003

A growth hormone receptor (GHR)- glycophosphatidylinositol (GPI) chimera acts as a receptor antagonist

Gavalas N , Pradhananga S , Beghadi C , Maamra M , Zarkesh-Esfahani H , Sayers J , Artymiuk P , Reymond C , Ross R

We have previously demonstrated that a truncated GHR lacking the cytoplasmic domain of the receptor acts as a dominant negative regulator of receptor signalling. Glycosylphosphatidylinositol (GPI) anchors are a common mechanism by which cells direct and anchor proteins in the cell membrane. We have generated a GHR extracellular domain-GPI fusion protein and tested its biological activity as a receptor antagonist. The extracellular domain of GHR (growth hormone binding protein-...