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‣ Posttranslational regulation of insulin-like growth factor binding protein-4 in normal and transformed human fibroblasts. Insulin-like growth factor dependence and biological studies.

Conover, C A; Kiefer, M C; Zapf, J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /03/1993 Português
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Insulin-like growth factor binding protein-4 (IGFBP-4) is a 24-26-kD protein expressed by a variety of cell types in vivo and in vitro. Treatment of normal adult human fibroblasts with 10 nM insulin-like growth factor II (IGF-II) for 24 h resulted in an 85% decrease in endogenous IGFBP-4, as assessed by Western ligand blot analysis of the conditioned medium. Incubation of human fibroblast-conditioned medium (HFCM) with IGF-II under cell-free conditions led to a similar loss of IGFBP-4. This posttranslationally regulated decrease in IGFBP-4 appeared to be due to a protease in HFCM: (a) It could be prevented with specific protease inhibitors or incubation at 4 degrees C; (b) proteolysis of recombinant human (rh) IGFBP-4 required HFCM; (c) immunoblotting and radiolabeling confirmed cleavage of IGFBP-4 into 18- and 14-kD IGFBP-4 fragments. The protease was specific for IGFBP-4, and was strictly dependent on IGFs for activation. IGF-II was the most effective of the natural and mutant IGFs tested, inducing complete hydrolysis of rhIGFBP-4 at a molar ratio of 0.25:1 (IGF/IGFBP-4). Simian virus 40-transformed adult human fibroblasts also expressed IGFBP-4 and IGFBP-4 protease, as well as an inhibitor of IGFBP-4 proteolysis. In biological studies...

‣ Studies on regulation of IGF (insulin-like growth factor)-binding protein (IGFBP) 4 proteolysis by pregnancy-associated plasma protein-A (PAPP-A) in cells treated with phorbol ester.

Sivanandam, Arun S; Mohan, Subburaman; Kita, Hirohito; Kapur, Sanjay; Chen, Shin-Tai; Linkhart, Thomas A; Bagi, Gyorgy; Baylink, David J; Qin, Xuezhong
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/04/2004 Português
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140.49934%
PAPP-A (pregnancy-associated plasma protein-A) is produced by hSFs (human skin fibroblasts) and hOBs (human osteoblasts) and enhances the mitogenic activity of IGFs (insulin-like growth factors) by degradation of IGFBP-4 (insulin-like growth factor-binding protein 4). PKC (protein kinase C) activation in these cells led to reduction in IGFBP-4 proteolysis. This study was undertaken to determine the mechanism by which activation of PKC suppresses IGFBP-4 proteolysis. Treatment of hSFs/hOBs with TPA (PMA; 100 nM) reduced IGFBP-4 proteolysis without significantly decreasing the PAPP-A level in the CM (conditioned medium). Immunodepletion of the proform of eosinophil major basic protein (proMBP), a known PAPP-A inhibitor, from CM of TPA-treated cells (TPA CM) failed to increase IGFBP-4 proteolytic activity. Transduction of hSFs with proMBP retrovirus increased the concentration of proMBP up to 30 ng/ml and led to a moderate reduction in IGFBP-4 proteolysis. In contrast, TPA treatment blocked IGFBP-4 proteolysis but failed to induce a detectable amount of proMBP in the CM. While proMBP overexpression led to the formation of a covalent proMBP-PAPP-A complex and reduced the migration of PAPP-A on SDS/PAGE, TPA treatment dose- and time-dependently increased the conversion of a approximately 470 kDa PAPP-A form (PAPP-A470) to a approximately 400 kDa PAPP-A form (PAPP-A400). Since unreduced PAPP-A400 co-migrated with the 400 kDa recombinant PAPP-A homodimer and since PAPP-A monomers from reduced PAPP-A470 and PAPP-A400 co-migrated on SDS/PAGE...

‣ Omeprazole Stimulates the Induction of Human Insulin-Like Growth Factor Binding Protein-1 through Aryl Hydrocarbon Receptor Activation

Murray, Iain A.; Perdew, Gary H.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Português
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130.35689%
5-Methoxy-2-{(4-methoxy-3,5-dimethyl-pyridin-2-yl)methylsulfinyl}-3H-benzoimidazole (omeprazole), a benzoimidazole-derived gastric H· /K· -ATPase proton pump inhibitor (PPI) extensively prescribed for the treatment of gastroesophageal acid reflux disease, can stimulate the expression of CYP1A1 via activation of the human aryl hydrocarbon receptor (hAhR) in an apparent nonligand-binding manner. Here, we have examined the effect of nonclassical, i.e., nonligand binding, AhR activation by omeprazole upon human insulin-like growth factor binding protein (hIGFBP)-1, a secreted phosphoprotein involved in regulation of insulin-like growth factor-I/II bioavailability and mitogenic activity. Analysis of the proximal promoter of the hIGFBP-1 gene reveals the presence of an aryl hydrocarbon binding/dioxin response element (DRE). Quantitative mRNA analysis revealed hIGFBP-1 expression to be responsive to both ligand (TCDD) and nonligand (omeprazole) modes of hAhR activation in the human hepatocarcinoma HepG2 cell line. Furthermore, mutagenesis of the DRE renders the hIGFBP-1 promoter unresponsive to both compounds in HepG2 cells. Likewise, small interfering RNA-mediated hAhR ablation inhibits TCDD and omeprazole-dependent hIGFBP-1 induction...

‣ Functional and Complementary Phosphorylation State Attributes of Human Insulin-like Growth Factor-Binding Protein-1 (IGFBP-1) Isoforms Resolved by Free Flow Electrophoresis

Nissum, Mikkel; Shehab, Majida Abu; Sukop, Ute; Khosravi, Javad M.; Wildgruber, Robert; Eckerskorn, Christoph; Han, Victor K. M.; Gupta, Madhulika B.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Publicado em /06/2009 Português
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130.4175%
Fetal growth restriction (FGR) is a common disorder in which a fetus is unable to achieve its genetically determined potential size. High concentrations of insulin-like growth factor-binding protein-1 (IGFBP-1) have been associated with FGR. Phosphorylation of IGFBP-1 is a mechanism by which insulin-like growth factor-I (IGF-I) bioavailability can be modulated in FGR. In this study a novel strategy was designed to determine a link between IGF-I affinity and the concomitant phosphorylation state characteristics of IGFBP-1 phosphoisoforms. Using free flow electrophoresis (FFE), multiple IGFBP-1 phosphoisoforms in amniotic fluid were resolved within pH 4.43–5.09. The binding of IGFBP-1 for IGF-I in each FFE fraction was determined with BIAcore biosensor analysis. The IGF-I affinity (K) for different IGFBP-1 isoforms ranged between 1.12e−08 and 4.59e−07. LC-MS/MS characterization revealed four phosphorylation sites, Ser(P)98, Ser(P)101, Ser(P)119, and Ser(P)169, of which Ser(P)98 was new. Although the IGF-I binding affinity for IGFBP-1 phosphoisoforms across the FFE fractions did not correlate with phosphopeptide intensities for Ser(P)101, Ser(P)98, and Ser(P)169 sites, a clear association was recorded with Ser(P)119. Our data demonstrate that phosphorylation at Ser119 plays a significant role in modulating affinity of IGFBP-1 for IGF-I. In addition...

‣ Circulating Insulin-like Growth Factor Binding Protein-4 (IGFBP-4) is not Regulated by Parathyroid Hormone and Vitamin D in vivo: Evidence from Children with Rickets

Bereket, Abdullah; Cesur, Yaşar; Özkan, Behzat; Adal, Erdal; Turan, Serap; Hanedan Onan, Sertaç; Döneray, Hakan; Akçay, Teoman; Haklar, Goncagül
Fonte: Galenos Publishing Publicador: Galenos Publishing
Tipo: Artigo de Revista Científica
Português
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150.1029%
Objective: Insulin-like growth factor binding protein-4 (IGFBP-4), inhibits IGF actions under a variety of experimental conditions. Parathyroid hormone (PTH), 1.25-hydroxy(OH)vitamin D, IGF-I, IGF-II and transforming growth factor (TGF)-b are the major regulators of IGFBP-4 production in vitro. However, little is known about the in vivo regulation of circulating IGFBP-4 in humans.

‣ Body Size in Early Life and Adult Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3

Poole, Elizabeth M.; Tworoger, Shelley S.; Hankinson, Susan E.; Schernhammer, Eva S.; Pollak, Michael N.; Baer, Heather J.
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
Português
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Body size in early life has been associated with breast cancer risk. This may be partly mediated through the insulin-like growth factor (IGF) pathway. The authors assessed whether birth weight, body fatness at ages 5 and 10 years, and body mass index (BMI; weight (kg)/height (m)2) at age 18 years were associated with plasma concentrations of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 in 6,520 women aged 32–70 years at blood draw from the Nurses’ Health Study (1990–2006) and Nurses’ Health Study II (1997–2005). Birth weight, body fatness in childhood, and BMI at age 18 years were inversely associated with adult IGF-1 levels. For example, IGF-1 levels were 11.9% lower in women who reported being heaviest at age 10 years than in those who were leanest at age 10 (P-trend < 0.0001). Further, women who reported their birth weight as ≥10 pounds (≥4.5 kg) (vs. <5.5 pounds (<2.5 kg)) had 7.9% lower IGF-1 levels (P-trend = 0.002). Women whose BMI at age 18 years was ≥30 (vs. <20) had 14.1% lower IGF-1 levels (P-trend < 0.0001). Similar inverse associations were observed for insulin-like growth factor binding protein 3. These observations did not vary by adult BMI or menopausal status at blood draw. These findings suggest that altered IGF-1 levels in adulthood may be a mechanism through which early-life body size influences subsequent breast cancer risk.

‣ Insulin-like Growth Factor Binding Protein-4 Differentially Inhibits Growth Factor-induced Angiogenesis*

Contois, Liangru W.; Nugent, Desiree P.; Caron, Jennifer M.; Cretu, Alexandra; Tweedie, Eric; Akalu, Abebe; Liebes, Leonard; Friesel, Robert; Rosen, Clifford; Vary, Calvin; Brooks, Peter C.
Fonte: American Society for Biochemistry and Molecular Biology Publicador: American Society for Biochemistry and Molecular Biology
Tipo: Artigo de Revista Científica
Português
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150.12989%
Background: We examined the impact of insulin-like growth factor binding protein-4 (IGFBP-4) on growth factor-induced angiogenesis in vivo.

‣ Increased expression of insulin-like growth factor-binding protein-3 is implicated in erectile dysfunction in two-kidney one-clip hypertensive rats after propranolol treatment

Zhou, Zhang-Yan; Yang, Zhong-Hua; Wang, Xing-Huan; Cao, Hong; Chen, Dong; Wang, Yong-Zhi; Zhou, Hai-Hong; Peng, Mou; Liu, Quan-Liang; Wan, Shao-Ping
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
Português
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130.32454%
This study aimed to investigate the role of insulin-like growth factor-binding protein-3 (IGFBP-3) in erectile dysfunction (ED) in two-kidney one-clip (2K–1C) hypertensive rats treated with the β-blocking agent propranolol. Adult male Wistar rats were randomly divided into three groups: a normal control group, a hypertensive control group and a propranolol treatment group (n=9). After 4 weeks of propranolol treatment, intracavernous pressure (ICP) responses to electrical stimulation of the cavernous nerves were evaluated. The expression of IGFBP-3 and insulin-like growth factor-1 (IGF-1) mRNA and protein in the rat cavernous tissue were detected by quantitative real-time PCR and Western blot, respectively. The concentration of cyclic guanosine monophosphate (cGMP) in the cavernous tissue was determined by enzyme-linked immunosorbent assay (ELISA). Cavernosal pressure in response to cavernous nerve stimulation was decreased 4 weeks after propranolol treatment (P<0.01, compared to the hypertensive control group). IGFBP-3 mRNA and protein expression was increased in the propranolol treatment group compared to the hypertensive control group (P<0.01), whereas IGF-1 expression was decreased in the propranolol treatment group compared to the hypertensive control group (P<0.01). In addition...

‣ Effects of acute and chronic food restriction on the insulin-like growth factor axis in the guinea pig

Sohlstrom, A.; Katsman, A.; Kind, K.; Grant, P.; Owens, P.; Robinson, J.; Owens, J.
Fonte: J ENDOCRINOLOGY LTD Publicador: J ENDOCRINOLOGY LTD
Tipo: Artigo de Revista Científica
Publicado em //1998 Português
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141.45401%
The effect of fasting (17-18 h) versus food restriction (70% for 80 +/- 13 days) on the IGF-IGF binding protein (BP) axis in female guinea pigs was studied and related to body weight, weight gain and food conversion efficiency. Circulating IGF-I was reduced in the fasted (13%) and food-restricted (50%) animals. IGF-II was only decreased (61%) in the food-restricted group. There was no effect of fasting on IGFBP-1 to -4 while IGFBP-1, -3 and -4 were reduced by 56%, 60% and 44% respectively, and IGFBP-2 increased by 72%, in the food-restricted group. Food restriction reduced the relative sizes of fat depots, spleen, liver, thymus and heart, increased those of adrenals, kidneys, pancreas, gastrointestinal tract, M. Biceps, M. Soleus and brain while those of uterus, lungs, thyroids and M. Gastrocnemius were unchanged. IGFBP-1 and -2 were negatively correlated to weight gain and food conversion efficiency in the ad libitum-fed group, while IGF-I, -II, IGFBP-1, -3 and -4 were positively correlated to body weight, weight gain and food conversion efficiency in the food-restricted group. The results show that acute and chronic food restriction have different consequences for the IGF-IGFBP axis. Furthermore, IGF-II as well as IGF-I are implicated in the control of body weight...

‣ Secretion in Escherichia coli & phage-display of recombinant insulin-like growth factor binding protein-2

Lucic, M.; Forbes, B.; Grosvenor, S.; Carr, J.; Wallace, J.; Forsberg, G.
Fonte: Elsevier Sci B.V. Publicador: Elsevier Sci B.V.
Tipo: Artigo de Revista Científica
Publicado em //1998 Português
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Insulin-like growth factors (IGFs) promote cell growth and differentiation. Their actions are regulated by six different, but related, binding proteins (IGFBPs). To investigate the molecular interactions between IGFs and IGFBPs, an Escherichia coli based production method and a phage display system has been developed. The cDNA for bovine IGFBP-2 was inserted between regions coding for the pelB signal sequence and geneIII product, g3p, of bacteriophage fd in a phagemid vector to generate pGF14. The coding sequences of IGFBP-2 and g3p were separated by an amber stop codon and a flexible linker containing the cleavage recognition site for H64A subtilisin. Using this system in BL21, a non-supE strain lacking ompT, most product, approximately 4 mg 1(-1) of IGFBP-2, was obtained in the growth medium. The bacterially derived IGFBP-2 had a correct N-terminal sequence, molecular mass on SDS-PAGE and the same affinity for IGF-1 and IGF-II as IGFBP-2 from mammalian cells. In a supE strain of E. coli, IGFBP-2 was produced as an IGF-binding fusion to g3p. Procedures for display and approximately 10000 fold enrichment of IGFBP-2 bearing phage using adsorption to IGF-II coated microtitre plates were developed. Thus IGFBP-2 can be secreted in E. coli and displayed on filamentous phage. These can be selectively enriched by binding to immobilised IGF-II.

‣ Circulating insulin-like growth factor (IGF)-1 and IGF binding proteins -1 and -3 and placental development in the guinea-pig

Roberts, C.; Kind, K.; Earl, R.; Grant, P.; Robinson, J.; Sohlstrom, A.; Owens, P.; Owens, J.
Fonte: W B Saunders Co Ltd Publicador: W B Saunders Co Ltd
Tipo: Artigo de Revista Científica
Publicado em //2002 Português
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141.23193%
Restricting maternal nutrition before and throughout pregnancy in the guinea-pig restricts foetal growth in part by altering placental structural determinants of substrate transfer function. The insulin-like growth factors have been implicated in mediating these changes. To assess the role of IGF-I in placental adaptation to maternal undernutrition, we examined the associations of circulating IGF-I and IGF binding proteins -1, -3 and -4 in the mother with placental structural development. In both mid- and late pregnancy, maternal food restriction reduced maternal plasma IGF-I by 56 per cent (P< 0.0005) and 50 per cent (P< 0.0005) respectively, and plasma IGFBP-3 by 47 per cent (P=0.03) and 55 per cent (P=0.002), respectively. Maternal plasma IGFBP-4 was reduced by 45 per cent (P=0.041) in food restricted guinea-pigs in mid-pregnancy but not late in pregnancy, while IGFBP-1 was unaltered at both stages. Late in pregnancy, food restriction reduced the ratio of maternal circulating IGF-I to IGFBP-1 by 52 per cent (P=0.011) and increased the ratio of IGF-I to IGFBP-3 in maternal plasma by 10 per cent (P=0.011). The relationships between the maternal IGF axis and structural correlates of placental function were assessed using pooled data from both ad libitum fed and food restricted animals. In mid-pregnancy...

‣ Circulating insulin-like growth factor-I and binding protein-3 and risk of prostate cancer

Severi, G.; Morris, H.; MacInnis, R.; English, D.; Tilley, W.; Hopper, J.; Boyle, P.; Giles, G.
Fonte: Amer Assoc Cancer Research Publicador: Amer Assoc Cancer Research
Tipo: Artigo de Revista Científica
Publicado em //2006 Português
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150.70448%
Some recent epidemiologic studies have failed to confirm positive associations between insulin-like growth factor-I (IGF-I) and the risk of prostate cancer observed in earlier studies but have reported suggestive evidence for a positive association between IGF-binding protein-3 (IGFBP-3) and prostate cancer risk, a result contradicting the earlier assumption that high levels of IGFBP-3 would be protective against prostate cancer. We tested the association between IGF-I and IGFBP-3 and prostate cancer risk by measuring the two peptides in plasma samples collected at baseline in a prospective cohort study of 17,049 men. We used a case-cohort design, including 524 cases diagnosed during a mean of 8.7 years follow-up and a randomly sampled subcohort of 1,826 men. The association between each peptide level and prostate cancer risk was tested using Cox models adjusted for country of birth and alcohol consumption. The risk of prostate cancer was not associated with baseline levels of IGF-I or the molar ratio IGF-I/IGFBP-3 (all odds ratios are between 0.82 and 1.08; P(trend) > or = 0.2), whereas the risk increased with baseline levels of IGFBP-3 (P(trend) = 0.008), the hazard ratio (HR) associated with a doubling of the concentration of IGFBP-3 being 1.70 (95% confidence interval...

‣ Contribution of residues A54 and L55 of the human insulin-like growth factor-II (IGF-II) A domain to Type 2 IGF receptor binding specificity

Forbes, B.; McNeil, K.; Scott, C.; Surinya, K.; Cosgrove, L.; Wallace, J.
Fonte: Harwood Acad Publ GMBH Publicador: Harwood Acad Publ GMBH
Tipo: Artigo de Revista Científica
Publicado em //2001 Português
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130.72621%
The underlying specificity of the interaction between insulin-like growth factor-II (IGF-II) and mammalian Type 2 insulin-like growth factor/cation-independent mannose 6 phosphate receptor (IGF2R) is not understood. We have mutated residues A54 and L55 of IGF-II in the second A domain helix to arginine (found in the corresponding positions of IGF-I) and measured IGF2R binding. There is a 4- and 3.3-fold difference in dissociation constants for A54R IGF-II and L55R IGF-II, respectively, and a 6.6-fold difference for A54R L55R IGF-II compared with IGF-II as measured by BlAcore analysis using purified rat IGF2R. This is also confirmed using cross-linking and soluble rat placental membrane receptor binding assays. Binding to the type I IGF receptor (IGF1R) and IGF binding protein-2 (IGFBP-2) is not altered. We can, therefore, conclude that residues at positions 54 and 55 in IGF-II are important for and equally contribute to IGF2R binding.

‣ Structure, dynamics and heparin binding of the C-terminal domain of insulin-like growth factor-binding protein-2 (IGFBP-2)

Kuang, Z.; Yao, S.; Keizer, D.; Wang, C.; Bach, L.; Forbes, B.; Wallace, J.; Norton, R.
Fonte: Academic Press Ltd Elsevier Science Ltd Publicador: Academic Press Ltd Elsevier Science Ltd
Tipo: Artigo de Revista Científica
Publicado em //2006 Português
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190.66463%
Insulin-like growth factor-binding protein-2 (IGFBP-2) is the largest member of a family of six proteins (IGFBP-1 to 6) that bind insulin-like growth factors I and II (IGF-I/II) with high affinity. In addition to regulating IGF actions, IGFBPs have IGF-independent functions. The C-terminal domains of IGFBPs contribute to high-affinity IGF binding, and confer binding specificity and have overlapping but variable interactions with many other molecules. Using nuclear magnetic resonance (NMR) spectroscopy, we have determined the solution structure of the C-terminal domain of IGFBP-2 (C-BP-2) and analysed its backbone dynamics based on 15N relaxation parameters. C-BP-2 has a thyroglobulin type 1 fold consisting of an α-helix, a three-stranded anti-parallel β-sheet and three flexible loops. Compared to C-BP-6 and C-BP-1, structural differences that may affect IGF binding and underlie other functional differences were found. C-BP-2 has a longer disordered loop I, and an extended C-terminal tail, which is unstructured and very mobile. The length of the helix is identical with that of C-BP-6 but shorter than that of C-BP-1. Reduced spectral density mapping analysis showed that C-BP-2 possesses significant rapid motion in the loops and termini...

‣ The N-terminal subdomain of insulin-like growth factor (IGF) binding protein 6. Structure and interaction with IGFs

Chandrashekaran, I.; Yao, S.; Wang, C.; Bansal, P.; Alewood, P.; Forbes, B.; Wallace, J.; Bach, L.; Norton, R.
Fonte: Amer Chemical Soc Publicador: Amer Chemical Soc
Tipo: Artigo de Revista Científica
Publicado em //2007 Português
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160.98128%
Insulin-like growth factor binding proteins (IGFBPs) modulate the activity and distribution of insulin-like growth factors (IGFs). IGFBP-6 differs from other IGFBPs in being a relatively specific inhibitor of IGF-II actions. Another distinctive feature of IGFBP-6 is its unique N-terminal disulfide linkages; the N-domains of IGFBPs 1-5 contain six disulfides and share a conserved GCGCC motif, but IGFBP-6 lacks the two adjacent cysteines in this motif, so its first three N-terminal disulfide linkages differ from those of the other IGFBPs. The contributions of the N- and C-domains of IGFBP-6 to its IGF binding properties and their structure-function relationships have been characterized in part, but the structure and function of the distinctive N-terminal subdomain of IGFBP-6 are unknown. Here we report the solution structure of a polypeptide corresponding to residues 1-45 of the N-terminal subdomain of IGFBP-6 (NN-BP-6). The extended structure of the N-terminal subdomain of IGFBP-6 is very different from that of the short two-stranded -sheet of the N-terminal subdomain of IGFBP-4 and, by implication, the other IGFBPs. NN-BP-6 contains a potential cation-binding motif; lanthanide ion binding was observed, but no significant interaction was found with physiologically relevant metal ions like calcium or magnesium. However...

‣ Insulin-like growth factor-I (IGF-I): Solution properties and NMR chemical shift assignments near physiological pH

Kuang, Z.; Yao, S.; McNeil, K.; Forbes, B.; Wallace, J.; Norton, R.
Fonte: Churchill Livingstone Publicador: Churchill Livingstone
Tipo: Artigo de Revista Científica
Publicado em //2009 Português
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140.66465%
OBJECTIVE: Insulin-like growth factor-I (IGF-I) plays important roles in normal growth and development, as well as in disease states, and its structure and function have been studied extensively using nuclear magnetic resonance (NMR) spectroscopy. However, IGF-I typically gives poor quality NMR spectra containing many broad peaks, because of aggregation at the protein concentrations generally required for NMR experiments as well as the internal dynamics of the molecule. The present study was undertaken to determine a reliable set of assignments under more physiological conditions. DESIGN: Several reports of chemical shift assignments have been published previously for IGF-I either bound to a ligand or at relatively low pH (approximately 3-4), but there are many contradictions among them, reflecting the poor behaviour of IGF-I. Low pH conditions are also suboptimal for the analysis of interactions between IGF-I and IGF binding proteins (IGFBP) or IGFBP fragments. Spectra were recorded at low concentrations in order to identify conditions of temperature and pH where all peaks could be observed. RESULTS: We show that good quality 2D (1)H-(15)N HSQC spectra of (15)N-labelled IGF-I can be obtained at pH 6 and 37 degrees C, much closer to physiological conditions...

‣ Insulin-like growth factor binding proteins: a structural perspective

Forbes, B.; McCarthy, P.; Norton, R.
Fonte: Frontiers Research Foundation Publicador: Frontiers Research Foundation
Tipo: Artigo de Revista Científica
Publicado em //2012 Português
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150.73263%
Insulin-like growth factor binding proteins (IGFBP-1 to -6) bind insulin-like growth factors-I and -II (IGF-I and IGF-II) with high affinity. These binding proteins maintain IGFs in the circulation and direct them to target tissues, where they promote cell growth, proliferation, differentiation, and survival via the type 1 IGF receptor. IGFBPs also interact with many other molecules, which not only influence their modulation of IGF action but also mediate IGF-independent activities that regulate processes such as cell migration and apoptosis by modulating gene transcription. IGFBPs-1 to -6 are structurally similar proteins consisting of three distinct domains, N-terminal, linker, and C-terminal. There have been major advances in our understanding of IGFBP structure in the last decade and a half. While there is still no structure of an intact IGFBP, several structures of individual N- and C-domains have been solved. The structure of a complex of N-BP-4:IGF-I:C-BP-4 has also been solved, providing a detailed picture of the structural features of the IGF binding site and the mechanism of binding. Structural studies have also identified features important for interaction with extracellular matrix components and integrins. This review summarizes structural studies reported so far and highlights features important for binding not only IGF but also other partners. We also highlight future directions in which structural studies will add to our knowledge of the role played by the IGFBP family in normal growth and development...

‣ Structure and interactions of the C-terminal domain of insulin-like growth factor binding protein-2 (IGFBP-2).

Kuang, Zhihe
Fonte: Universidade de Adelaide Publicador: Universidade de Adelaide
Tipo: Tese de Doutorado
Publicado em //2006 Português
Relevância na Pesquisa
140.62247%
Insulin-like growth factor binding protein-2 (IGFBP-2) is the largest member of a family of six proteins (IGFBP-I to 6) that bind insulin-like growth factors-I and -II (IGF-I/II) with high affinities. IGFBP molecules contain three domains of approximately equal length: the conserved cysteine-rich amino- and carboxyl-terminal domains, which are joined by a variable linker domain. The C-terminal domains of IGFBPs not only contribute to high-affinity IGF binding, but also confer binding specificity and have overlapping but variable interactions with many other molecules. At the time this project commenced, there was limited information on the structure-function relationships of the C-domain of IGFBPs. In this thesis, the following N- and C-domain fragments were prepared in sufficient quantities for NMR studies: unlabelled, ¹⁵N-labelled and ¹⁵N/¹³c-labelled ¹⁸³⁻²⁸⁹IGFBP-2 (C-BP-2), unlabelled ¹⁴¹⁻²⁸⁹IGFBP -2 (Large-C-BP-2), and unlabelled and ¹⁵N-labelled ¹⁻¹³⁸IGFBP-2 (N-BP-2). The IGF binding abilities of these fragments were assessed using BIAcore and cross-linking methods. Overall, the results indicated that C-BP-2 binds IGFs to only a limited extent, although the differences in IGF binding affinities among C-BP-2...

‣ Insulin-like Growth Factor I (IGF-I), IGFBP-3 und Alkalische Phosphatase (AP) bei idiopathischem Wachstumshormonmangel (iGHD) und Neurosekretorischer Dysfunktion (NSD) vor und während der Therapie mit Wachstumshormon (GH); Insulin-like Growth Factor I (IGF-I), IGFBP-3 and Alkaline Phosphatase (AP) in children with idiopathic Growth Hormone Deficiency (iGHD) and Neurosecretoric Dysfunction (NSD) before and during therapy with human Growth Hormone (GH)

Rist, Roland
Fonte: Universität Tübingen Publicador: Universität Tübingen
Tipo: Dissertation; info:eu-repo/semantics/doctoralThesis
Português
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Es wurden 116 überwiegend präpubertäre Kinder über einen Zeitraum von einem bzw. vier Jahren untersucht, die an der Universitäts-Kinderklinik Tübingen wegen idiopathischem Wachstumshormonmangel (iGHD) oder wegen Neurosekretorischer Dysfunktion (NSD) mit ca. 0,6 IU rekombinantem Wachstumshormon pro kg Körpergewicht und Woche behandelt wurden. Die Diagnose iGHD wurde gestellt bei einer mittleren nächtlichen Spontansekretion von <3,5ng/ml GH in Verbindung mit <10ng/ml GH in zwei GH-Stimulationstests mit Arginin oder Insulin. Die Diagnose NSD entsprechend bei <3,5ng/ml bzw. >10ng/ml GH. Es wurden folgende Parameter untersucht: Körpergröße/ -gewicht, Body-Mass-Index, Knochenalter, Insulin-like Growth Factor I (IGF-I), IGFBP-3 und Alkalische Phosphatase (AP). Die Körpergröße war bei beiden Diagnosen zu Therapiebeginn deutlich erniedrigt (iGHD: MW=-3,7+/-1,3SD; NSD: MW=-3,0+/-0,7SD). Die iGHD-Patienten zeigten zu Therapiebeginn signifikant niedrigere Werte für die Körpergröße, die IGF-I- und die IGFBP-3-Serumkonzentration (p<0,001). Während des ersten Jahres konnte bei beiden Diagnosen ein signifikanter Anstieg der Parameter Körpergröße, Körpergewicht, IGF-I, IGFBP-3 und AP festgestellt werden (p<0,001 außer AP[NSD]: p=0...

‣ Insulin-like growth factor-1, insulin-like growth factor binding protein-3 and lobule type in the Nurses' Health Study II

Shen, Dejun; Pollak, Michael N; Rice, Megan Siobhan; Tamimi, Rulla May; Connolly, James Leo; Collins, Laura Christine; Rosner, Bernard Alfred; Hankinson, Susan Elizabeth; Tworoger, Shelley Slate
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Português
Relevância na Pesquisa
130.60195%
Introduction: Previous research in the Nurses' Health Study (NHS) and the NHSII observed that, among women diagnosed with benign breast disease (BBD), those with predominant type 1/no type 3 lobules (a marker of complete involution) versus other lobule types were at lower risk of subsequent breast cancer. Studies in animal models suggest that insulin-like growth factor-1 (IGF-1) may inhibit involution of lobules in the breast; however, this has not been studied in humans. Methods: We conducted a cross-sectional study among 472 women in the NHSII who were diagnosed with biopsy-confirmed proliferative BBD between 1991 and 2002 and provided blood samples between 1996 and 1999. A pathologist, blinded to exposure status, classified lobule type in normal adjacent tissue on available biopsy slides according to the number of acini per lobule. For each participant, the pathologist determined the predominant lobule type (that is, type 1, type 2, or type 3) and whether any type 1 or any type 3 lobules were present. Lobule type was then classified as: predominant type 1/no type 3 lobules, which is suggestive of complete involution; or other lobule types. Multivariate logistic models were used to assess the associations between plasma IGF-1, insulin-like growth factor binding protein-3 (IGFBP-3)...