Insulin-like growth factor-binding protein-3 (IGFBP-3) blocks the effects of asthma by negatively regulating NF-κB signaling through IGFBP-3R-mediated activation of caspases.

Insulin-like growth factor-binding protein-3 (IGFBP-3) is a multifunctional protein known for modulating mitogenic and metabolic actions of IGFs as well as exerting a variety of biological actions not involving IGFs. Here, we show that IGFBP-3 blocks specific physiological consequences of asthma in an IGF-independent manner in vitro and in vivo. IGFBP-3 treatment effectively reduced all physiological manifestations of asthma examined in vivo (airway hyper-responsiveness, cellular and pathological changes in bronchoalveolar lavage fluid and lung tissue, and expression of numerous proinflammatory molecules).

Transglutaminase 2 kinase activity facilitates protein kinase A-induced phosphorylation of retinoblastoma protein.

Transglutaminase 2 (TG2, tissue transglutaminase) is a multifunctional protein involved in cross-linking a variety of proteins, including retinoblastoma protein (Rb). Here we show that Rb is also a substrate for the recently identified serine/threonine kinase activity of TG2 and that TG2 phosphorylates Rb at the critically important Ser780 residue. Furthermore, phosphorylation of Rb by TG2 destabilizes the Rb.

Ethnicity, insulin resistance, and inflammatory adipokines in women at high and low risk for vascular disease.

Objective: We sought to compare the relationship between body composition, insulin resistance, and inflammatory adipokines in Aboriginal Canadian women, who are at high risk of vascular disease, with white women.

Research Design And Methods: A subgroup of the First Nations Bone Health Study population, consisting of 131 Aboriginal women and 132 matched white women, was utilized. Body composition was determined by whole-body dual X-ray absorptiometry, and blood analytes were measured after an overnight fast.

Variations in parametrial white adipose tissue mass during the mouse estrous cycle: relationship with the expression of peroxisome proliferator-activated receptor-gamma and retinoic acid receptor-alpha.

Estrogen and progestin participate in the regulation of adipose tissue metabolism, and peroxisome proliferator-activated receptor-gamma (PPARgamma) and retinoic acid receptor-alpha (RXRalpha) are absolutely required for adipose tissue development. The present study is to investigate the changes in parametrial fat mass and expression of PPARgamma and RXRalpha during estrous cycle in mice. Parametrial white adipose tissues (WAT), inter-scapula brown adipose tissues, and uteri from female mice were weighed.

Prohibitin binds to C3 and enhances complement activation.

Prohibitin (PHB1) is a multifunction protein that is released in lipid droplets from adipocytes and possibly other cells and is detectable in the circulation. We used crosslinking, immunoprecipitation and proteomic analysis to investigate binding partners for circulating PHB1. Crosslinking of PHB1 to serum resulted in two complexes of approximately 150 and 100 kDa, which contained both PHB1 and fragments of C3.

Plasma adipokines and body composition in response to modest dietary manipulations in the mouse.

Objective: The relationship between adipokine levels and body composition has not been carefully examined. Most studies in humans are cross-sectional, and the few studies in mice have been restricted to a comparison of control animals with markedly obese, insulin-resistant mice. Our objective was to study changes in adipokine levels and body composition in response to modest dietary intervention.

Phosphorylation of transglutaminase 2 by PKA at Ser216 creates 14-3-3 binding sites.

Transglutaminase 2 (TG2) is a multifunctional ubiquitous enzyme which is present in various cellular compartments and is subject to phosphorylation by PKA. To better understand the relevance of PKA induced phosphorylation of TG2, we performed pull-down assays using phosphorylated biotinylated-TG2(209-223) peptides spanning PKA induced phosphorylation sites as a bait. Subsequent analysis of pull-down protein by SDS-PAGE and LC/MS identified 14-3-3epsilon as the binding partner for TG2 which was further confirmed by immunoblotting with 14-3-3 specific antiserum.

The Prohibitins: emerging roles in diverse functions.

The prohibitins, Phb1 and Phb2 are highly conserved proteins in eukaryotic cells that are present in multiple cellular compartments. Initial investigations focused on the role of Phb1 as an inhibitor of cell proliferation hence the original name prohibitin. However both proteins appear to have a diverse range of functions and recent evidence suggests that the prohibitins have very similar but as yet only partially understood functions.

Canadian guidelines for the management of adult growth hormone deficiency.

Purpose: To develop guidelines for the management of growth hormone (GH) deficiency in Canadian adults to facilitate rational use of GH in appropriate indications.

Methods: The guidelines were developed by group of endocrinologists and an endocrine specialist nurse with an interest in neuroendocrine disorders, representing all regions of Canada and practicing in a variety of settings. A steering committee with broad expertise undertook a systematic review of the evidence relating to adult GHD and GH replacement.

Insulin-like growth factor (IGF) binding protein-3 attenuates prostate tumor growth by IGF-dependent and IGF-independent mechanisms.

IGF binding protein (IGFBP)-3 inhibits cell growth and promotes apoptosis by sequestering free IGFs. In addition IGFBP-3 has IGF-independent, proapoptotic, antiproliferative effects on prostate cancer cells in vitro. Expression of the large T-antigen (Tag) under the long probasin promoter (LPB) in LPB-Tag mice results in prostate tumorigenesis.

Prohibitin attenuates insulin-stimulated glucose and fatty acid oxidation in adipose tissue by inhibition of pyruvate carboxylase.

Prohibitin (PHB-1) is a highly conserved protein involved in mitochondrial biogenesis and function. It is secreted in lipid droplets from adipocytes and is present in the circulation. In adipose tissue it functions as a membrane receptor and can target binding partners to the mitochondria.

Phosphorylation of histones by tissue transglutaminase.

Tissue transglutaminase 2 (TG2) has recently been shown to have intrinsic serine/threonine kinase activity. Since histones are known to be cross-linked by TG2, we investigated whether histones are also substrates for TG2 kinase activity. TG2 was able to phosphorylate H1, H2A, H2B, H3, and H4 histones in vitro.

Insulin-like growth factor binding proteins in development.

IGFBPs regulate growth and development by regulating IGF transport to tissues and IGF bioavailability to IGF receptors at cell membrane level. IGFBP excess leads predominantly to inhibition of IGF action and growth retardation with impaired organogenesis. Absence of human and also mouse ALS leads to decreased IGF-I levels in circulation and causes mild growth retardation.

The p53 oncoprotein is a substrate for tissue transglutaminase kinase activity.

Increased expression and activity of the ubiquitous enzyme, tissue transglutaminase (TG2), is consistently seen in a variety of models of apoptosis. The p53 oncoprotein is also involved in apoptosis. Here we investigated the interaction of TG2 with p53 and show that the p53 is a substrate for the recently identified serine/threonine kinase activity of TG2.

Inhaled insulin improves glycemic control when substituted for or added to oral combination therapy in type 2 diabetes: a randomized, controlled trial.

Background: Patients with type 2 diabetes who do not achieve glycemic control with oral agent therapy eventually require insulin.

Objective: To determine the effect on glycemic control of inhaled insulin alone or added to dual oral therapy (insulin secretagogue and sensitizer) after failure of dual oral therapy.

Design: Open-label, randomized, controlled trial.

The effects of the insulin-like growth factor-I aptamer, NBI-31772, on glucose homeostasis in the mouse.

The majority of insulin-like growth factor-I (IGF-I) in the adult rodent circulation is bound to high affinity IGF binding proteins. We investigated the changes in IGF-I clearance, blood glucose and plasma insulin levels, and tissue 2-deoxyglucose uptake after intravenous administration of the IGF aptamer, NBI-31772, which selectively competes with IGF-I for binding to the IGFBPs, but has no effect at the IGF-I receptor. Clearance of 125I-IGF-I was significantly increased in NBI-31772-treated mice compared with vehicle-treated mice (t1/2 = 45.

The effects of growth hormone status on circulating levels of vascular growth factors.

Background: Vascular growth factors are important not only in angiogenesis but also for the maintenance of normal endothelial integrity and function. Elevated levels of vascular endothelial growth factor (VEGF), angiopoietin-2, hepatocyte growth factor (HGF), endostatin and angiogenin have been associated with endothelial dysfunction and atherosclerosis. Both acromegaly and growth hormone deficiency (GHD) are associated with endothelial dysfunction and changes in blood vessel morphology.

Prohibitin: a potential target for new therapeutics.

Prohibitin (PHB) is localized to the mitochondria where it might have a role in the maintenance of mitochondrial function and protection against senescence. There is considerable controversy concerning the function of nuclear-localized PHB. PHB has potential roles as a tumor suppressor, an anti-proliferative protein, a regulator of cell-cycle progression and in apoptosis.

The effects of insulin-like growth factor binding protein-3 (IGFBP-3) on T47D breast cancer cells enriched for IGFBP-3 binding sites.

To investigate insulin-like growth factor (IGF)-independent effects of IGF binding protein-3 (IGFBP-3), T47D cells were enriched for a population of cells that expressed binding sites for biotinylated-IGFBP-3 by panning on streptavidin-coated plate. Proliferation of cell enriched for IGFBP-3 binding sites was significantly inhibited by IGFBP-3, whereas IGFBP-3 had no significant effect on the non-enriched cell population. Enriched and non-enriched cells were equally responsive to IGF-I, TGF-beta and EGF.

Overexpression of gly56/gly80/gly81-mutant insulin-like growth factor-binding protein-3 in transgenic mice.

IGF-independent effects of IGF-binding protein-3 (IGFBP-3) have been demonstrated in vitro; however, the physiological significance of these effects in vivo is unclear. We generated two transgenic (Tg) mouse strains that overexpress a human Gly56/Gly80/Gly81-mutant IGFBP-3 cDNA. This mutant has a markedly reduced affinity for the IGFs, but retains the IGF-independent effects.

Sexual dimorphism and regulation of resistin, adiponectin, and leptin expression in the mouse.

Objective: To examine gender differences and hormonal regulation of resistin, adiponectin, and leptin.

Research Methods And Procedures: Plasma levels were measured, and mRNA expression in perigonadal fat was quantified by RNase protection assays.

Results: Plasma resistin declined with age despite an increase in adiposity in both genders.

Tissue transglutaminase has intrinsic kinase activity: identification of transglutaminase 2 as an insulin-like growth factor-binding protein-3 kinase.

Tissue transglutaminase (TG2) is a ubiquitous enzyme that cross-links glutamine residues with lysine residues, resulting in protein polymerization, cross-linking of dissimilar proteins, and incorporation of diamines and polyamines into proteins. It has not previously been known to have kinase activity. Recently, insulin-like growth factor-binding protein-3 (IGFBP-3) has been reported to be phosphorylated by breast cancer cell membranes.

Insulin-like growth factor binding protein-3 interacts with autocrine motility factor/phosphoglucose isomerase (AMF/PGI) and inhibits the AMF/PGI function.

Autocrine motility factor/phosphoglucose isomerase (AMF/PGI) was identified as a binding partner for insulin-like growth factor binding protein-3 (IGFBP-3) in solubilized T47D and MCF-7 human breast cancer cell membranes. The interaction between AMF/PGI and IGFBP-3 was verified by cross-linking biotinylated IGFBP-3 to intact cells. After solubilization of the membranes, the biotinylated complexes were precipitated with streptavidin-agarose conjugate and analyzed by SDS-PAGE.

The effects of GH replacement in adult GH-deficient patients: changes in body composition without concomitant changes in the adipokines and insulin resistance.

Background: Growth hormone deficiency (GHD) in adult life has been associated with increased central adiposity, decreased insulin sensitivity, dyslipidaemia and increased risk of cardiovascular disease. The effects of GH replacement on adiponectin and resistin, adipokines which have a role in modulating insulin sensitivity have not been previously reported.

Aim: To examine the effects of GH replacement on adipokine levels and insulin resistance in GHD patients.