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At least 19 recordsLinked to original sources
PubMed2000

Insulin-like growth factor (IGF)-I stimulates IGF-I and type 1 IGF receptor expression in cultured rat granulosa cells: autocrine regulation of the intrafollicular IGF-I system.

A growing body of information documents the existence of a complete rat intrafollicular insulin-like growth factor (IGF)-I system replete with a ligand (IGF-I), a receptor (type 1 IGF receptor) IGF binding proteins (4 and 5), and IGFBP-directed endopeptidases (4 and 5). Previous studies have established the ability of IGF-I to promote the elaboration of granulosa cell-derived IGFBP-5 and to suppress the activity of granulosa cell-derived IGFBP-5-directed endopeptidase. It was the purpose of this article to examine the effects of treatment with IGF-I on the other components of the intrafollicular IGF system, i.e., IGF-I itself and the type 1 IGF-receptor. Granulosa cells, obtained by follicular puncture from 25-d-old estrogen-primed rats were cultured in polystyrene tubes for 72 h under serum-free conditions, in the absence or presence of the indicated agents. At the conclusion of each experiment, media were discarded, and RNA was extracted and subjected to an RNase protection assay. Treatment of cultured rat granulosa cells with IGF-I resulted in a significant 1.8-fold increase in the steady-state levels of IGF-I mRNA. No effect was noted on the total cellular DNA content thereby arguing against the possibility that the relative increase in IGF-I transcripts can be ascribed to a possible treatment-induced increase in cell number in culture. The IGF-I effect was apparent (p < 0.05) at IGF-I doses as low as 1 ng/mL, minimal additional increments being noted thereafter. Treatment with insulin and des (1-3) IGF-I proved equally effective, producing 2.0- and 2.6-fold increases, respectively, thereby suggesting that the IGF-I effect may be mediated via the type 1 IGF receptor. Treatment with IGF-I also resulted in a significant (p < 0.005) increase in type 1 IGF receptor expression (2.3-fold increase), the first significant effect being noted at the 30 ng/mL dose level. Similar results obtained for insulin and des (1-3) IGF-I thereby suggest that the ability of IGF-I to upregulate the expression of its own receptor is probably type 1 IGF receptor-mediated. Taken together, these findings indicate that treatment of estrogen-primed granulosa cells with IGF-I will result in upregulation of the steady-state levels of transcripts corresponding to IGF-I itself and to its type 1 IGF receptor. These observations emphasize the importance of positive autoregulatory phenomena as determinants of the intrafollicular content of IGF-I and its receptor.

Animals↗
PubMed2003

Levels of plasma insulin-like growth factor I (IGF I), IGF II, IGF binding proteins, type 1 IGF receptor and growth hormone binding protein in community-dwelling elderly subjects with no malnutrition and no inflammation.

Plasma samples from community-dwelling subjects aged 65 to 92 presenting no malnutrition and no inflammation (as assessed by albumin, transthyretin, CRP, and orosomucoid levels and BMI) were compared to those of healthy controls aged 20 to 65 to determine the effect of aging on the IGF system. Concentrations of IGF I, IGF II and IGFBP3 significantly decreased, and those of GHBP slightly increased with age from 20 to 92 years (n=327 r=-0.64 p<0.0001; n=45 r=-0.44 p<0.003; n=91 r=-0.23 p<0.03 and n=61 r=0.26; p<0.05 respectively). Western immunoblotting showed that the proteolysis of IGFBP3 was not significantly different in elderly and younger subjects. The affinity of the IGF type 1 receptor for IGF I was moderately lower (Ki=0.56 0.2 vs 0.33 0.1, nM respectively; p<0.005) and the number of binding sites was moderately higher (10.4 1.5 vs 8.1 1.9 binding sites/cell, respectively; p<0.03) in the elderly than in the younger adults. Our results suggest that the age-related decline in plasma levels of IGF I, IGF II and IGFBP3 occurs independently from malnutrition and inflammation processes. GHBP plasma levels, which reflect the number of GH receptors at the level of the liver, do not decline in our malnutrition-free elderly population, and thus are not involved in the decline of IGF I plasma levels with age. In the elderly, affinity and number of type 1 IGF receptor were close to those of younger subjects; the decline in IGF I plasma levels may account for the small rise in the number of type 1 IGF receptors binding sites per cell.

Aged↗
PubMed2001

Insulin-like growth factor (IGF) I down-regulates type 1 IGF receptor (IGF 1R) and reduces the IGF I response in A549 non-small-cell lung cancer and Saos-2/B-10 osteoblastic osteosarcoma cells.

The insulin-like growth factor type 1 receptor (IGF 1R) mediates the acute metabolic effects of IGF I as well as IGF I-stimulated cell proliferation and protection from apoptosis. IGF binding proteins (IGFBPs) can modulate these responses. We, therefore, investigated whether intrinsic IGFBPs interfere with IGF I-induced regulation of IGF 1R expression and with the biological response to IGF I in two human tumor cell lines, the non-small-cell lung cancer cell line A549 and the osteoblastic osteosarcoma cell line Saos-2/B-10. We compared the growth rates, IGFBP production, IGF I binding characteristics, IGF 1R protein and mRNA levels, and the acute IGF I response (stimulation of glycogen synthesis) after pretreatment of the cells in serum-free medium with or without added IGF I or medium supplemented with 5% fetal calf serum (FCS). In contrast to A549 cells, which produce IGF I and significant amounts of IGFBPs, survival and proliferation of Saos-2/B-10 cells, which do not produce IGF I or significant amounts of IGFBPs, depended on the addition of exogenous IGF I. IGF I increased the concentration of IGFBP-2 and -3 and decreased the concentration of IGFBP-4 in the medium of A549 cells. As compared to FCS, IGF I pretreatment in both cell lines decreased the number of specific IGF I binding sites, down-regulated total and membrane IGF 1R protein, and largely reduced or abolished the acute IGF I response without affecting IGF 1R mRNA levels. The data suggest that the IGF 1R protein of the two cell lines is translationally and/or posttranslationally down-regulated by its ligand in the presence and in the absence of locally produced IGFBPs and that the cell lines have retained this negative feedback to counteract IGF I stimulation.

Apoptosis↗
PubMed1998

Dysregulation of the type 1 IGF receptor as a paradigm in tumor progression.

The Type 1 IGF receptor plays a critical role in cell progression. During normal ontogeny it is expressed by every proliferating cell, where it functions as a potent cell survival agent. Disruption of the Type 1 IGF receptor gene by homologous recombination results in severely growth retarded animals which invariably die at birth. Most importantly, fibroblasts derived from mice embryos lacking the receptor cannot be transformed by any of a number of oncogenes, indicating that the Type 1 IGF receptor has a crucial role in the transformation process. Consistently, the receptor displays potent mitogenic and antiapoptotic activities [corrected]. A number of transcription factors have been identified that control the expression of the IGF receptor promoter, thus stimulating cellular proliferation. On the other hand, certain tumour suppressors including p53 and WT1 were shown to repress the activity of the IGF receptor promoter. Mutant forms of these and other tumour suppressors are potentially impaired in their ability to suppress expression of the IGF receptor gene, thus helping to expand neoplastic populations.

Animals↗
PubMed1999

In vitro and in vivo responses to short-term recombinant human insulin-like growth factor-1 (IGF-I) in a severely growth-retarded girl with ring chromosome 15 and deletion of a single allele for the type 1 IGF receptor gene.

OBJECTIVES: Patients with single allele defects in the gene encoding the type 1 IGF receptor have been reported to have growth failure, but fibroblasts from affected patients have not exhibited insensitivity to the effects of IGF-I in vitro. The in vitro and in vivo responses to short-term recombinant human IGF-I (rhIGF-I) in a severely growth-retarded girl with ring chromosome 15 and deletion of a single allele for the type 1 IGF receptor gene have been investigated. DESIGN AND PATIENT: The child exhibited prenatal and severe post-natal growth failure, and delayed psychomotor development. Southern blotting revealed a 50% reduction in IGF-I receptor DNA, and in an RNase protection assay (RPA), a quantitatively similar reduction in steady-state mRNA for type 1 IGF receptor. rhIGF-I was administered in graded doses of 40, 60 and 80 microg/kg twice daily by subcutaneous injection for periods of 2-2.5 days each. RESULTS: During rhIGF-I treatment, mean urinary nitrogen excretion was unchanged and urinary calcium rose to 60% greater than in the pre-treatment period. rhIGF-I injections produced only a modest decrease in indices of GH secretion, assessed by frequent (every 20 min) sampling over periods of 12 h. There was no significant difference between the mean GH concentrations during rhIGF-I treatment (5.32 +/- 6.2 mU/l) compared with that before rhIGF-I treatment (8.46 +/- 10.2 mU/l). Mean IGFBP-3-values were increased (4.5 mg/l before vs. 5.4 mg/l during rhIGF-I). TSH values after injection of TRH were not significantly reduced by IGF-I (mean of all values, 18.6 mU/l vs. 15.5 mU/l during rhIGF-I treatment). In vitro binding of radiolabelled IGF-I to the patient's fibroblasts was less than that bound by control fibroblasts (patient, 0.69% binding by 248 000 cells, vs. 1.41% binding by 260 000 fibroblasts from an age-matched control). However, the patient's fibroblasts exhibited a growth response in vitro to the addition of IGF-I in a fashion similar to that of control fibroblasts. CONCLUSIONS: These studies show evidence in each of the indices examined of in vivo resistance to IGF-I and suggest that the growth retardation observed in such patients may be the direct result of the absence of one of the alleles encoding the type 1 IGF receptor.

Blotting, Southern↗
PubMed1997

Differential regulation of tissue insulin-like growth factor-binding protein (IGFBP)-3, IGF-I and IGF type 1 receptor mRNA levels, and serum IGF-I and IGFBP concentrations by growth hormone and IGF-I.

The aims of this investigation were (1) to examine IGF-binding protein-3 (IGFBP-3) mRNA levels in candidate tissues which might be important sources for blood IGFBP-3 (liver and skin) and in a target tissue for IGF-I action (skeletal muscle), and (2) to examine the effects of a single dose (500 micrograms) of GH or IGF-I on IGFBP-3 message levels in these tissues since temporal responses (4, 8 and 24 h after the single subcutaneous dose of peptide to GH-deficient dwarf rats) would indicate which peptide is the primary modulator of IGFBP-3 synthesis. Circulating IGF-I and IGFBP-3 concentrations were significantly increased (P < 0.05) by IGF-I and GH. GH treatment increased liver IGFBP-3 mRNA levels by 4 h (P < 0.001 over the 24 h) whereas IGF-I had no effect. Similarly, GH, but not IGF-I, increased muscle IGFBP-3 mRNA levels (P < 0.001 for the 24 h study period). However, both IGF-I and GH induced increases in skin IGFBP-3 mRNA abundance throughout the 24 h period (P < 0.001 and P < 0.01 respectively) and skin IGFBP-3 message abundance was greater that in the liver. Liver IGF-I mRNA levels were, as expected, increased after GH and tended to decrease after IGF-I treatment; muscle IGF-I mRNA was increased by GH (P < 0.001) and, interestingly, progressively increased by IGF-I (P < 0.05 for the 24 h period); skin IGF-I mRNA levels were unchanged by both peptides. The IGF-I induced increase in serum IGFBP-3 concentrations in the absence of an increase in hepatic IGFBP-3 mRNA levels and a paucity of liver IGF-I type 1 receptor mRNA imply that other sources of IGFBP-3 protein or synthesis must exist. The response of skin IGFBP-3 mRNA levels to both GH and IGF-I suggests that other cell types, such as fibroblast-derived cells, could be more important than the liver in the regulation of circulating reservoir IGFBP-3 in certain circumstances. In contrast to some current suggestions, the rapid and consistent GH-induced increase in IGFBP-3 message levels in all tissues studied implies that GH might have a direct function in the regulation of IGFBP-3 synthesis.

Animals↗
PubMed2001

IGF type 1 receptor ligand binding characteristics are altered in a subgroup of children with intrauterine growth retardation.

The IGFs, IGF-I and IGF-II, regulate fetal growth by activating IGF type 1 receptors (IGF-IR). We aimed to quantify the binding of IGF-I to its cognate receptors in intrauterine growth-retarded children (IUGR). We measured the affinity of the erythrocyte IGF-IR and the number of IGF-IR receptors in 17 children with retarded growth (mean height, -2.7 SD), normal levels of GH, and a history of idiopathic intrauterine growth retardation (height at birth, -10 to -2 SD; mean, -3.1 SD). These children had reduced receptor affinity (Kd = 0.47 nM; P < 0.01) and more receptors per cell [binding capacity (Bmax) = 11.7 binding sites/cell; P < 0.05)] compared with control children (Kd = 0.32 nM; Bmax = 7.8 binding sites/cell). Moreover, the distributions of Kd and Bmax suggested that there were two groups of IUGR children. Group 1 included subjects with normal receptor binding function (Kd = 0.36 nM; Bmax = 8.2 sites/cell) and normal levels of circulating IGF-I. Group 2 comprised children with low receptor affinity (Kd = 0.56 nM) and increased receptor number (Bmax = 14.7 sites/cell). This group showed significantly decreased IGF-I levels (-2.1 SD; P < 0.01). We investigated these IGF-IR binding parameters in two additional groups of growth-retarded children (Turner syndrome and patients with chronic renal failure), in whom the IGF-I axis was not believed to be the primary cause, and found that Kd and Bmax were normal or nearly normal. We also measured IGF-IR binding parameters in 4 Seckel syndrome patients with IUGR and severely retarded growth (mean height, -7.9 SD). Their receptor affinity was reduced, but not statistically different, from that in controls, and their receptor number was normal, whereas IGF-I levels were elevated. Our results suggest heterogeneous alterations in IGF-IR binding function in IUGR patients.

Adolescent↗
PubMed1989

The C region of human insulin-like growth factor (IGF) I is required for high affinity binding to the type 1 IGF receptor.

We have produced and characterized the binding properties of three structural analogs of human insulin-like growth factor I (hIGF-I). These analogs are [1-62]hIGF-I, an analog lacking the carboxyl-terminal 8-amino acid D region of hIGF-I; [1-27, Gly4, 38-70]hIGF-I, an analog in which residues 28-37 of the C region of hIGF-I are replaced by a 4-reside glycine bridge; and [1-27,Gly4,38-62]hIGF-I, an analog with the C region glycine replacement and a D region deletion. The removal of the D region of hIGF-I has little effect on binding to the type 1 and type 2 insulin-like growth factor (IGF) receptors. [1-62]hIGF-I has 2-fold higher affinity for the insulin receptor and 4-fold higher affinity for IGF serum-binding proteins. The replacement of the C region of hIGF-I with a four-glycine span results in a 30-fold loss of affinity for the type 1 IGF receptor. However this analog has near normal affinity for the type 2 IGF receptor, the insulin receptor, and IGF serum-binding proteins. Incorporating the C region glycine replacement and the D region deletion into one analog does not affect binding to either the type 2 receptor or to IGF serum-binding proteins. As predicted from the single deletion analogs [1-27,Gly4,38-62]hIGF-I has reduced affinity for the type 1 IGF receptor (approximately 40-fold) and increased affinity for the insulin receptor (5-fold). These data indicate that determinants in the C region of hIGF-I are involved in maintaining high affinity binding to the type 1 IGF receptor and that neither the C region nor the D region are required for high affinity binding to the type 2 IGF receptor or to IGF serum-binding proteins.

Amino Acid Sequence↗
PubMed2001

Insulin-like growth factor (IGF) binding protein-3 inhibits type 1 IGF receptor activation independently of its IGF binding affinity.

Insulin-like growth factor binding proteins (IGFBPs) regulate the cellular actions of the IGFs owing to their strong affinities, which are equal to or stronger than the affinity of the type 1 IGF receptor (IGF-IR), the mediator of IGF signal transduction. We recently found that IGFBP-3 modulates IGF-I binding to its receptor via a different mechanism possibly involving conformational alteration of the receptor. We have now investigated the effects of IGFBP-3 on the initial steps in the IGF signaling pathway. MCF-7 breast carcinoma cells were preincubated with increasing concentrations of IGFBP-3 and then stimulated with IGF-I, des(1-3)IGF-I, or [Q(3)A(4)Y(15)L(16)]-IGF-I, the latter two being IGF-I analogs with intact affinity for the type 1 IGF receptor, but weak or virtually no affinity for IGFBPs. Stimulation of autophosphorylation of the receptor and its tyrosine kinase activity was dose-dependently depressed. At 2.5 nM, IGFBP-3 provoked more than 50% inhibition of the stimulation induced by 3 nM des(1-3)IGF-1 and, at 10 nM, more than 80% inhibition. Similar results were obtained with [Q(3)A(4)Y(15)L(16)]-IGF-I. Cross-linking experiments using iodinated or unlabeled IGFBP-3 and anti-IGF-IR antibodies indicated that the inhibitory effects do not involve direct interaction between IGFBP-3 and IGF-IR. The inhibition appeared to be specific to IGFBP-3, because IGFBP-1 and IGFBP-5 at 10 nM had no significant effect. Also, inhibition was restricted to the IGF receptor, because IGFBP-3 failed to inhibit the tyrosine kinase activity of the insulin receptor stimulated by physiological concentrations of insulin. Our results provide the first demonstration that IGFBP-3 can specifically modulate the IGF-I signaling pathway independently of its IGF-I-binding ability. They also reveal a regulatory mechanism specific to the type 1 IGF receptor, with no effect on insulin receptor activation.

Breast Neoplasms↗
PubMed1996

The avian IGF type 1 receptor: cDNA analysis and in situ hybridization reveal conserved sequence elements and expression patterns relevant for the development of the nervous system.

Insulin-like growth factor type 1 receptor (IGF-1R) is a tyrosine kinase with a key role in development. The primary structure of IGF-1R is known for mammalian species, but not for birds. The avian embryo, however, provides an ideal system for the experimental study of neurogenesis. We therefore cloned the complete coding sequence of the chicken IGF-1R from a cDNA library and analyzed its embryonic expression by Northern blot and in situ hybridization. The deduced chicken IGF-1R precursor of 1363 amino acids was 85% identical to human IGF-1R and did not show deletions or insertions in critical positions, when compared to its mammalian homologues. Notably, all cysteine residues in the extracellular domains, and 15 of the 17 N-linked glycosylation sites found in human IGF-1R were also present in the chicken receptor. An 11 kb transcript was abundant in developing nervous tissues, kidney, pancreas and the gastrointestinal tract. The early in situ expression patterns in 20-somite embryos revealed high levels of IGF-1R mRNA in the neuroepithelia, notochord and somites. At embryonic day 4 (E4), high concentrations of IGF-1R transcripts were found again primarily in the neuroepithelia and, to a lesser degree, in the sensory ganglia and diverse mesenchymal derivatives. During the second half of embryonic development, IGF-1R expression in the CNS was particularly abundant in telencephalic regions, including the olfactory bulb, hippocampus, striatum and piriform cortex, and also in the optic tectum and cerebellum. By the use of cDNA cloning and in situ hybridization this study reveals conserved amino acid sequence elements between birds and mammals, and developmental expression patterns that are compatible with an important role of this receptor in growth, differentiation and maturation of the avian CNS.

Animals↗
PubMed2000

Expression of mRNA encoding IGF-I, IGF-II and type 1 IGF receptor in bovine ovarian follicles.

IGFs regulate gonadotrophin-stimulated proliferation and differentiation of granulosa and theca cells in vitro. However, the detailed pattern of mRNA expression of IGFs in bovine follicles remains controversial. The objectives of this study were therefore to describe the temporal and spatial pattern of expression of mRNA encoding IGF-I, IGF-II and the type 1 IGF receptor in bovine follicles in vivo. The expression of mRNA encoding IGF-II was detected in theca tissue from around the time of antrum formation up to and during the development of dominance. No IGF-II mRNA expression was detected in granulosa cells. In the majority of follicles we were unable to detect mRNA encoding IGF-I in either granulosa or theca tissue from follicles at any stage of development. Occasionally low amounts of mRNA encoding IGF-I were detected in the theca externa and connective tissue surrounding some follicles. Type 1 IGF receptor mRNA was detected in both granulosa and theca cells of preantral and antral follicles. Expression was greater in granulosa tissue compared with theca tissue. We also measured IGF-I and -II mRNA in total RNA isolated from cultured granulosa and theca cells using reverse transcriptase PCR. In contrast to the in vivo results, IGF-II mRNA was detected in both granulosa and theca tissue. IGF-I mRNA was detected in theca tissue and in very low amounts in granulosa cells. Using a specific IGF-I RIA we were unable to detect IGF-I immunoreactivity in granulosa conditioned cell culture media. Using immunohistochemistry we detected IGF-I immunoreactivity in some blood vessels within the ovarian stroma. We conclude from these results that IGF-II is the principal intrafollicular IGF ligand regulating the growth of bovine antral follicles. In preantral follicles the expression of mRNA encoding type 1 IGF receptor but absence of endogenous IGF-I or -II mRNA expression, highlights a probable endocrine mechanism for the IGF regulation of preantral follicle growth.

Animals↗
PubMed1996

Influence of blockers for the estrogen receptor (ER) and type 1 IGF-receptor on the levels of ER, ER mRNA and IGF-I mRNA in the rat uterus.

The effects on the uterine concentration of the estrogen receptor (ER), ER mRNA and IGF-I mRNA were monitored in ovariectomized (OVX) rats treated with blockers for the estrogen receptor (ER) (ICI 182780) or the type 1 IGF receptor (H-1356), alone or in combination with estradiol (E2). The hormone-mediated increase in uterine wet weight after E2 treatment was prevented by a simultaneous injection of ICI 182780. The levels of IGF-I mRNA and ER mRNA increased in rats given estradiol (E2), but not in those also receiving ICI 182780. The level of uterine ER was decreased in all animals that received ICI 182780. H-1356 (H) given as a continuous infusion decreased the estradiol-induced increase in uterine wet weight 24 h after a single E2 injection, but not 48 h after the first (of two) E2 injections. The IGF-I mRNA was increased in the E2 treated group after 24 h, and in both the E2 and H + E2 treated groups after 48 h. The ER mRNA was increased in the E2 treated group after 24 h, but not after 48 h. When H-1356 was given as two single injections and estradiol was or was not administered together with the second injection, the uterine wet weight was not increased as in the group receiving E2 only. The levels of IGF-I mRNA as well as ER mRNA were increased both after E2 and H + E2 treatment. In conclusion, the uterine growth stimulated by E2 was prevented by simultaneous treatment with ICI 182780. In addition a type 1 IGF-receptor blocker, which is an IGF-I analogue inhibiting the autophosphorylation of the receptor, also prevented the hormone-induced uterine growth after 24 h, but not after 48 h, when given as a continuous infusion. The results imply that the growth process stimulated by estradiol utilizes the ER receptor, and also the type 1 IGF-receptor during the first 24 h after E2 treatment.

Animals↗
PubMed2001

Regulation of Id2 gene expression by the type 1 IGF receptor and the insulin receptor substrate-1.

The Id family of helix-loop-helix proteins is known to be involved in the proliferation and differentiation of several types of cells. The type 1 IGF receptor (IGF-IR) induces either proliferation or differentiation in 32D cells, a murine hemopoietic cell line, depending on the availability of the appropriate substrates for the receptor. We have previously reported that the IGF-IR regulates the expression of the Id2 gene in 32D cells. We now show that the IGF-IR controls the increase in Id2 gene expression through at least three pathways. These three pathways originate from the tyrosine residue at 950, a domain in the C-terminus, and the activation of the insulin receptor substrate-1 (IRS-1) by the receptor. IRS-1 is the preponderant signal, and its effect on Id2 gene expression requires a functional phosphotyrosine binding domain. With wild-type IRS-1, Id2 gene expression is increased, even in those cells that express IGF-I receptors defective in Id2 signaling. Rapamycin, an inhibitor of p70(S6K), a downstream effector of IRS-1 signaling, partially inhibits (but does not completely abrogate) the increase in Id2 gene expression. A mutant IRS-1 with a deletion of the Pleckstrin domain is as effective as wild-type IRS-1 in up-regulating Id2 gene expression. In addition, it seems to increase the stability of p70(S6K). Our results indicate that the IGF-IR regulates Id2 gene expression through different pathways. At least in 32D cells, increased Id2 gene expression seems to correlate more with inhibition of differentiation than with proliferation.

Animals↗
PubMed2000

IGF-I stimulates chemotaxis of human neuroblasts. Involvement of type 1 IGF receptor, IGF binding proteins, phosphatidylinositol-3 kinase pathway and plasmin system.

SH-SY5Y human neuroblastoma cells express IGF receptors, IGFs and IGF binding proteins (IGFBPs), and provide a model for studying the role of the IGF system in human neuronal development. We investigated the effect of IGF-I and des(1-3)IGF-I on the motility of SH-SY5Y cells by a cell migration assay based on the assessment of the number of cells which migrated across 8 microm pore size membranes and around an agarose drop. IGF-I and des(1-3)IGF-I stimulated neuroblast chemotaxis in a dose-dependent manner. Treatment of cells with these agents for 24 h resulted in a significant increase (IGF-I by 70% and des(1-3)IGF-I by 90%; P<0. 0001) in cell motility relative to control conditions. Addition of monoclonal antibody against type 1 IGF receptor (alpha-IR3), significantly (P<0.05) reduced the cell motility induced by IGF-I (by 30%) and des(1-3)IGF-I (by 70%). Wortmannin, a specific inhibitor of phosphatidylinositol (PI)-3 kinase intracellular signalling, also reduced the IGF-stimulated cell migration (by over 40%, P<0.01), indicating a key role of the PI-3 kinase pathway in mediating the IGF effect on neuroblast migration. Finally, cell treatment with plasminogen (PLG) markedly enhanced neuroblast migration (by over 200%, P<0.01), whereas incubation with the PLG inhibitor 4-(2-aminoethyl)-benzenesulphonyl fluoride reduced cell motility (by 80%, P<0.01), thus suggesting an involvement of PLG-dependent IGFBP proteolysis in the regulation of neuroblast motility. In conclusion, IGF-I is a potent stimulator of neuroblast migration through the activation of type 1 IGF receptor and the PI-3 kinase intracellular pathway. IGFBPs and the plasmin system seem to play a role in cell motility, although the nature and the extent of their involvement has yet to be elucidated.

Antibodies, Monoclonal↗
PubMed1999

Follicular and luteal expression of insulin-like growth factors I and II and the type 1 IGF receptor in the bovine ovary.

The localization of mRNAs for insulin-like growth factors I (IGF-I) and II (IGF-II) and the type 1 IGF receptor (IGF-1R) in bovine follicles and corpora lutea was determined using in situ hybridization on sectioned ovaries collected from nonpregnant, cyclic Holstein cows in either the follicular (n = 3) or luteal (n = 5) phases of the cycle. Concentrations were measured as absorbance units of individual regions or follicles from autoradiographs. There was intense follicular expression of mRNAs encoding IGF-II and IGF-1R. For mRNA encoding IGF-II, expression was significantly higher in smaller follicles (< 5 mm diameter, P < 0.01) and, in this size range, expression was significantly greater in healthy compared with atretic follicles (P < 0.01). For mRNA encoding IGF-1R, there was no effect of size but concentrations were again significantly greater in healthy compared with atretic follicles of < 5 mm. In medium (5-10 mm) and large (> 10 mm) follicles, there was no effect of health for expression of either IGF-II or IGF-1R. mRNA encoding IGF-II was found exclusively in the theca, whereas mRNA encoding IGF-1R was confined to the granulosa layer. IGF-I expression was not detectable in 83% of the 53 follicles examined. In the remaining 17% of follicles, expression was very low and was unrelated to size or state of atresia. mRNAs encoding IGF-I, -II and IGF-1R were all present in the corpus luteum, whereas only those for IGF-II and IGF-1R were found in ovarian stroma. These data indicate that the insulin-like growth factors play a significant role in follicular and luteal development in the bovine ovary. Locally produced IGF-II is probably an important regulator of follicular growth, whereas most of the IGF-I present in follicular fluid is likely to be derived from the circulation.

Animals↗
PubMed1995

Localization of messenger ribonucleic acids for insulin-like growth factor I (IGF-I), IGF-II, and the type 1 IGF receptor in the ovine ovary throughout the estrous cycle.

The distribution pattern of messenger RNAs (mRNAs) for insulin-like growth factor I (IGF-I), IGF-II, and the type 1 IGF receptor and the detection of IGF-binding sites in sections of ovine ovary were demonstrated using in situ hybridization and autoradiography. Ovaries were collected from 30 ewes at time points throughout the estrous cycle. Luteal IGF-II mRNA and IGF-binding site concentrations altered significantly during the cycle, peaking on day 8 (midluteal phase; P < 0.01) and day 15 (late luteal phase; P < 0.001), respectively. In contrast, mRNA expression for IGF-I and the type 1 IGF receptor in the corpus luteum was low and did not vary. IGF-binding sites and mRNAs for IGF-II and the type 1 IGF receptor were also present at low and constant concentrations in ovarian stroma. There was no detectable follicular expression of IGF-I mRNA, although there were high concentrations of IGF-II and the type 1 IGF receptor mRNAs, which both varied significantly with follicular size (P < 0.001 and 0.01, respectively), with the highest concentrations in small follicles (< 2 mm in diameter). Follicular IGF-II expression was confined to the theca, whereas the type 1 IGF receptor was present in both theca and granulosa. IGF-binding site concentrations were significantly higher (P < 0.01) in atretic than healthy follicles, but were uninfluenced by follicular size. These results suggest that IGF-II, in contrast to IGF-I, appears to be the most significant IGF in luteal and, particularly, follicular development in the ewe.

Animals↗
PubMed1995

Developmental changes in the expression patterns of IGFs, type 1 IGF receptor and IGF-binding proteins-2 and -4 in perinatal rat lung.

The insulin-like growth factors (IGF-I and IGF-II), their receptors and binding proteins (IGFBPs) are endogenously expressed in a number of tissues including the lung during fetal and neonatal development. This endogenous autocrine/paracrine IGF 'system', together with endocrine sources, contributes to the regulation of lung cell proliferation. We investigated the expression of the mRNAs encoding IGF-I, IGF-II, the type 1 IGF receptor (IGF-T1R) and two IGF-binding proteins (IGFBP-2 and IGFBP-4) in rat lung during the perinatum. These were compared in lung with surfactant apoprotein A (Sp-A) mRNA levels. mRNA in extracts of fetal tissues collected between day 17 of gestation (17f) and day 9 after birth (9d) was estimated by Northern blot or RNase protection analysis. At day 20 of gestation IGF-I, IGF-T1R and IGFBP-4 mRNA levels were higher in lung than liver (all P < 0.01), whereas IGF-II and IGFBP-2 mRNA levels were higher in liver than lung (each P < 0.02). The expression of IGF-1, IGFBP-2 and IGFBP-4 in lung was high before birth (days 17-20f) but decreased to low levels at days 21f, 22f or at birth (1d) but increased in the neonatal lung. IGF-II expression in lung was high at 17f but decreased before birth and remained low after birth. The IGF-T1R was expressed at moderate levels before birth, decrease before birth but peaked at days 2-5 after birth. The decrease in expression of these growth regulators before birth expression of these growth regulators before birth was matched by an increased in Sp-A expression which was clearly seen at day 20f, peaked at 1d and then was clearly seen at day 20f, peaked at 1d and then was maintained at high levels after birth. Primary cell cultures of 18f lung epithelia express IGFBP-2 while fibroblasts from the same animals express only IGFBP-4. Cells grown from 22f lung tissue express IGFBP-2 and IGFBP-4 at lower levels, behaving in vitro as they do in vivo. The contrasting levels of expression of different components of the IGF system in the fetal lung and liver indicate organ-specific regulation. IGFBP-2 and IGFBP-4 expression in different cell types within lung but with similar temporal changes suggests cell-specific regulation, perhaps by a common agent. The patterns by a common agent. The patterns of expression of IGF-I, IGF-T1R, IGFBP-2 and IGFBP-4, but not IGF-II, in developing lung correspond to previously described phasic changes in lung cell proliferation rates. The nadir in expression of these four major components of the lung IGF system occurs in the saccular phase when the lung begins to differentiate, probably under the influence of certain endocrine agents.

Aging↗