Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To delinate regions of IGFBP-3 involved in ligand and cell-surface binding. DNAs encoding human IGFBP-3 [1-264] and several variants were transfected into CHO cells. Of three deletion (delta) mutants. IGFBP-3 [1-88], [1-184], and [delta 89-184], none bound IGF-I tracer by ligand blotting, although all were detectable by immunoblotting. No ALS binding was detectable, as predicted by the lack of IGF binding. Normal-sequence IGFBP-3 associated with the CHO cells and was partly displaceable by IGF-I. Whereas IGFBP-3 [1-88] and [1-184] failed to cell-associate, the non-IGF-binding central deletion variant [delta 89-184] did associate with CHO cells but was not displaced by IGF-I. To further examine the role of the carboxy-terminal domain in cell-association, the basic sequence IGFBP-3 [228-232] (KGRKR) was altered to the corresponding IGFBP-1 residues MDGEA, a major charge reversal. This variant showed reduced IGF-I binding, and bound ALS with decreased affinity as determined by Scatchard analysis. It showed no cell binding, implicating the basic domain in cell-association. We conclude that, whereas the central and carboxy-terminal domain deletions fail to bind IGF-I, the ability to cell associate requires the carboxy-terminal but not the central domain. Specifically, the basic region [228-232] is essential for cell binding, and also affects IGF-I binding, and independently, ALS affinity.
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PMID:Modulation of human IGF binding protein-3 activity by structural modification. 881 64

The insulin-like growth factors (IGFs) and their binding properties (IGFBPs) are believed to play important roles in the growth and development of the human fetus. They have been implicated in the pathophysiology of pre-eclampsia. In this study we have characterized the developmental regulation, in normal and pre-eclamptic pregnancies, of IGFs and IGFBPs in maternal serum, neonatal serum and amniotic fluid. In neonatal cord serum IGFBP-1, -2 and -6 decreased with increasing gestational age. In contrast, the ternary complex and its components, IGF-I, IGFBP-3 and ALS increased with gestation. We show that while ALS is an important limiting factor for ternary complex formation in the fetal circulation, there is a fraction of IGFBP-3 which is unable to form this complex. IGFs and IGFBPs in the maternal and fetal circulation were similar in normal and pre-eclamptic pregnancies.
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PMID:Developmental regulation of circulating insulin-like growth factor-binding proteins in normal pregnancies and in pre-eclampsia. 881 92

Over the last several years, the authors have studied the relationship of insulin-like growth factors (IGFs) and the insulin-like growth factor binding proteins (IGFBPs) in the circulation in a number of clinical settings. Patterns have emerged that seem to be characteristic of various conditions. In aging, there are marked decreases in IGF-I and -II, normal levels of IGFBP-3, and marked increases in IGFBP-1 in serum. Using ligand blotting and an IGFBP-3 proteolysis assay, BP-3 is intact. Based on native gel electrophoresis, IGFBP-1 is in its most highly phosphorylated state in those elders who have high IGFBP-1 levels. This pattern is slightly different in catabolic conditions such as AIDS (wasting in adults; failure to thrive in children), uncontrolled diabetes mellitus, trauma, and severe burns. In these conditions, serum levels of IGF-I and -II are markedly diminished, IGFBP-3 levels are also decreased, and IGFBP-1 levels are markedly increased. In addition, there is increased proteolysis of IGFBP-3 (AIDS failure to thrive, uncontrolled diabetes mellitus) and disruption of the ternary complex with decreased levels of ALS (AIDS wasting and burns). IGFBP-1 is in its most highly phosphorylated state in all catabolic conditions studied. Thus, the alterations in the circulating levels of IGFs and the changes in the physical state of the IGFBPs may lead to decreased anabolic activity and be a part of the mechanism of increased catabolism and wasting.
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PMID:IGFBP-3. Functional and structural implications in aging and wasting syndromes. 944 38

The IGFs are believed to be important in pregnancy and are implicated in the pathophysiology of pre-eclampsia. In adults the IGFs circulate primarily with IGF-binding protein-3 (IGFBP-3) and an acid-labile glycoprotein (ALS) in a 140 kDa complex which limits IGF bioavailability. Less than 10% of IGFBP-3 is in lower molecular weight forms. We have investigated the developmental regulation of the IGF/IGFBP system in normal and pre-eclamptic pregnancies with particular emphasis on the IGFBP-3 ternary complex. Circulating levels of IGF-I, IGFBP-3 and ALS, and their degree of association in the ternary complex in the fetus increased with gestational age. In neonatal serum from deliveries <35 weeks' gestation IGFBP-3 was predominantly in 30-50 kDa form(s) and ALS was a limiting factor for ternary complex formation. In serum from deliveries >35 weeks both ALS and IGFs were limiting but approximately 25% of IGFBP-3 was unable to form the ternary complex even in the presence of excess ALS and IGF-I. Serum IGFBP-1, -2 and -6 concentrations tended to decrease with increasing gestational age. In pre-eclamptic pregnancies, amniotic fluid IGFBP-2, -3 and -6 levels decreased with gestational age while IGFBP-1 levels did not show the normal decline. We speculate that the endocrine IGF system develops in the fetus during the third trimester of pregnancy when ALS levels increase.
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PMID:Regulation of insulin-like growth factor-binding protein-3 ternary complex formation in pregnancy. 979 67

Serum levels of insulin and insulin-like growth factors and their binding proteins (IGFs and IGFBPs, respectively) are changed in human neurodegenerative diseases of very different etiology, such as Alzheimer's disease, amyotrophic lateral sclerosis, or cerebellar ataxia. However, the significance of these endocrine disturbances is not clear. We now report that in two very different inherited neurodegenerative conditions, ataxia-telangiectasia (AT) and Charcot-Marie-Tooth 1A (CMT-1A) disease, serum levels of IGFs are also altered. Both types of patients have increased serum IGF-I and IGFBP-2 levels, and decreased serum IGFBP-1 levels, while only AT patients have high serum insulin levels. Furthermore, serum IGFs are also changed in three different animal models of neurodegeneration: neurotoxin-induced motor discoordination, diabetic neuropathy, and hereditary cerebellar ataxia. In these three models, serum insulin levels are significantly decreased, serum IGF-I and IGFBP-1, -2, and -3 are decreased in diabetic and neurotoxin-injected rats, while serum IGFBP-1 is increased in hereditary ataxic rats. Altogether, these observations indicate that a great variety of neurodegenerative diseases show endocrine perturbations, resulting in changes in serum IGFs levels. These perturbations are disease-specific and are probably due to metabolic and endocrine derangements, nerve cell death, and sickness-related disturbances associated to the neurodegenerative process. Our observations strongly support the need to evaluate serum IGFs in other neurodegenerative conditions.
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PMID:Neurodegeneration is associated to changes in serum insulin-like growth factors. 1111 63

Peroxisome proliferator-activated receptor alpha (PPARalpha) plays a central role in glucose and lipid homeostasis. Mice lacking PPARalpha(-/-) have a sexually dimorphic phenotype. We have characterized the IGF system in wild type and PPARalpha-/- mice. In normal mice fasting IGF-I and the IGFBP-3 ternary complex were 2-fold higher in males than in females. PPARalpha influenced the IGF/IGFBP response to feeding, particularly in males. Compared to wild type, male PPARalpha-/- mice had 40% lower total fasting IGF-I concentrations, decreased ALS and less IGFBP-3 ternary complex formation, but within 4 h of refeeding there was an increase in IGF-I and IGFBP-3 ternary complex to values similar to controls. Circulating IGFBP protease activity was induced in male PPARalpha-/- mice during refeeding. IGFBP-1 and insulin concentrations were higher in males than females, and were increased by PPARalpha knockout, suggesting significant hepatic insulin resistance. We speculate that gender differences in the IGF system contribute to the PPARalpha-/- phenotype.
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PMID:Responses of insulin-like growth factor (IGF)-I and IGF-binding proteins to nutritional status in peroxisome proliferator-activated receptor-alpha knockout mice. 1173 49

Insulin-like growth factor 1 (IGF-1, somatomedin C) belongs to a family of polypeptide hormones, which are structurally close relatives of insulin. Circulating IGF-1 is synthesised in the liver. Serum level of somatomedin is regulated by: growth hormone (GH), insulin and nutrition. It is also produced locally by most tissues, where it acts in auto- and paracrine manner. IGF-1 takes part in regulating growth after binding to IGF receptor during embryonic development and after birth. In adults somatomedin plays a role in the process of regeneration, mainly in the case of connective tissue. It is also a weak mitogen for most cultured cells and it can act like insulin. Somatomedin circulates in plasma in complex with a family of binding proteins. 85-95% of total IGF-1 is found in the complex consisting of IGF-1, binding protein 3 and ALS. This complex is a store of IGF and limits the access of somatomedin to specific receptors. After binding with IGFBP-1, IGFBP-2 and IGFBP-6, IGF-1 passes through epithelium and reaches the target cells. The serum concentration of this protein appears to be inversely related to insulin level. IGFBP-1 can modulate IGF growth-promoting effect. IGF and its binding proteins are important in the diagnosis and treatment of some pituitary diseases, catabolic states such as malnutrition, burns, AIDS, polytrauma and tumors with hypoglikemia. Insulin-like growth factors may be involved in the etiopathogenesis of diabetes and in diabetes complications. Abnormalities in functioning of GH-IGF-1 axis are regarded as a cause of the growth retardation in children with poor metabolic control of type 1 diabetes, insulin-resistance, dawn phenomenon and fat disorders. rhIGF has been used in the treatment of some diseases bringing positive results.
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PMID:[Insulin-like growth factor 1 (somatomedin C) and its binding proteins 1 and 3 in children with special consideration of diabetes]. 1281 85

IGF-I and IGF-II (IGFs) form higher molecular weight complexes with specific binding proteins (IGFBP-1 to -6). These complexes are referred to as binary complexes consisting of IGF-I or IGF-II and one IGFBP, or as ternary complexes each consisting of either of IGF-I or IGF-II, IGFBP-3 or -5, and an acid-labile subunit known as ALS. Ternary complex formation restricts the IGFs to the circulation and prolongs their half-life. Recently, the development of an animal model for ALS deficiency (the ALS-KO mouse) and the identification of a patient with an inactivating mutation in the IGFALS gene have provided the opportunity to assess the physiological role of this protein in the circulating IGF system. ALS deficiency has no effect on fetal growth in both the ALS-KO mice and the ALS-deficient patients. A modest reduction in post-natal growth in the null ALS mice and in the ALS-deficient patients was observed. The plasma concentrations of IGF-I and IGFBP-3 were markedly reduced both in ALS-KO mice and in the ALS-deficient patients. Basal GH levels remained normal in the ALS-KO mice and moderately increased in the ALS-deficient patients. Insulin-resistance was present in the ALS-deficient patients but not in the ALS-KO mice. Reduced bone mineral density (BMD) was present in mice and human ALS deficiency. Phenotypic features of complete ALS deficiency, that are very similar in mouse and human, include: a) the inability to form ternary complex, b) the small growth impairment in spite of the marked reduction in circulating IGF-I, and c) the reduction in BMD. On the other hand, insulin resistance and pubertal delay were observed only in human ALS deficiency. These findings underlie the important physiological role of ALS in the maintenance of the circulating IGF-I reservoir. Both models will be useful in identifying the respective roles of plasma and locally derived IGF-I in regulating metabolism and growth of specific tissues.
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PMID:Acid-labile subunit deficiency: phenotypic similarities and differences between human and mouse. 1611 75

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. Although IGFBP KO mice demonstrate relatively minor phenotypes, the possibility of compensatory mechanisms that mask the phenotypic manifestation of lack of individual binding proteins needs to be further investigated. Recent studies of hepatic regeneration in IGFBP-1 KO mice and also with mutant IGFBP-3 Tg mice provide some limited support for the existence of IGF-independent mechanism of action in vivo.
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PMID:Insulin-like growth factor binding proteins in development. 1637 Jan 36

Supplementation of cattle diets with n-3 polyunsaturated fatty acids (n-3 PUFA) has been suggested to have positive effects on fertility. In addition, the actions of the insulin-like growth factor (IGF) system both systemically and locally have been shown to influence reproductive processes. The objective of this study was to evaluate the effect of dietary n-3 PUFA supplementation on hepatic and endometrial expression of IGF signalling genes in cattle. Beef heifers were supplemented with a rumen protected source of either a saturated fatty acid (palmitic acid; CON) or high n-3 PUFA diet (n-3 PUFA) for 45 days before slaughter and tissue recovery. Transcription level of candidate IGF signalling genes was measured by reverse transcription quantitative real-time PCR (RT-qPCR) in total RNA isolated from uterine endometrial and liver tissue from seven CON and seven n-3 PUFA supplemented animals. Compared to controls, mRNA abundance in n-3 PUFA liver tissues was higher for IGF-2R, IGFBP-1 and IGFBP-5 (P < 0.05); lower for GHR-1A (P < 0.05); and unchanged for IGF-1, IGF-2, IGF-1R, IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-6, ALS and GHR(total) (P > 0.05). Compared to controls, mRNA abundance in n-3 PUFA endometrial tissues was higher for IGF-2, IGF-1R, IGF-2R and IGFBP-2 (P < 0.05); lower for IGF-1, IGFBP-3 and IGFBP-6 (P < 0.05); and unchanged for IGFBP-1, IGFBP-4, IGFBP-5 and GHR(total) (P > 0.05). Thus, dietary supplementation of cattle with n-3 PUFA affects transcription of genes involved in IGF signalling, in a tissue dependent fashion.
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PMID:Effect of dietary n-3 polyunsaturated fatty acid supplementation on bovine uterine endometrial and hepatic gene expression of the insulin-like growth factor system. 2111 66


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