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PubMed2006

The relationship of insulin-like growth factor-II, insulin-like growth factor binding protein-3, and estrogen receptor-alpha expression to disease progression in epithelial ovarian cancer.

PURPOSE: The insulin-like growth factor (IGF) system plays important roles in cancer; blocking IGF signaling has been shown to have therapeutic effects on tumor growth. Many studies have focused on the effect of IGF-I, but few have addressed IGF-II. To assess the role of IGF-II in cancer, we analyzed IGF-II expression in ovarian cancer and examined its association with disease characteristics and prognosis. EXPERIMENTAL DESIGN: Included in the study were 215 patients with primary epithelial ovarian cancer. Fresh tumor specimens were collected during surgery, and the patients were followed for a median of 31 months. Total RNA was extracted from the tumor and analyzed for IGF-II, IGF binding protein 3 (IGFBP-3), and estrogen receptor-alpha expressions using quantitative reverse transcription PCR. Survival analysis was done to examine the associations of IGF-II with disease progression. RESULTS: IGF-II expression was found to be higher in tumors with poor prognosis; this included tumors with advanced stage, poor differentiation, serous histology, and large residual lesions. Patients with high IGF-II had elevated risk for disease progression and death, although the significance became less evident when the analysis was adjusted for clinical and pathologic variables. IGFBP-3 expression was higher in less aggressive tumors, but was not associated with disease progression. The expression of estrogen receptor-alpha had no effect on survival. CONCLUSION: This study found evidence that IGF-II expression is associated with disease progression, suggesting that IGF-II and IGF signaling are potential targets for ovarian cancer treatment. The study also indicates that IGF-II and IGFBP-3 have limited value in prognosis because of their strong associations with disease stage and tumor grade.

Adult↗

PubMed1993

Insulin-like growth factor II increases the rate of sciatic nerve regeneration in rats.

A slow rate of nerve regeneration conspires together with atrophy and degeneration of denervated organs to increase the risk of permanent disability following injury to the mammalian peripheral nervous system. Therefore, it is of both practical and theoretical interest to identify those endogenous factors that determine the spontaneous velocity of nerve regeneration, and to discover exogenous factors which hold promise for augmenting the rate. We report that locally infused insulin-like growth factor II significantly increases the speed of sensory axon regeneration in rat sciatic nerves. It appeared that 1 microgram/ml insulin-like growth factor II acted through insulin-like growth factor receptors, because a comparable concentration of insulin had little effect. Furthermore, there was a sustained reduction in regeneration rate when an anti-insulin-like growth factor II antiserum was continuously infused near a window in the epineurium located just below a site of nerve crush, indicating that the spontaneous regeneration rate was continuously dependent on endogenous insulin-like growth factor activity. These results show that exogenously administered insulin-like growth factor II can increase the rate of peripheral nerve regeneration, and that the endogenous insulin-like growth factors in nerves are required to maintain the normal rate of regeneration. These in vivo data complement previous observations showing that insulin-like growth factors can increase neurite outgrowth in cultured neurons, and that insulin-like growth factor II gene expression is correlated with synapse development. They further support the hypothesis that insulin-like growth factors play a role in nerve regeneration.

Animals↗

PubMed1983

The interaction of salicylate and vitamin K in synthesis of Factor II (prothrombin).

The effects of sodium salicylate on synthesis of a vitamin K-dependent plasma coagulation protein, Factor II (prothrombin) was studied using the isolated rat liver perfused for 10 hours in vitro. Cumulative synthesis of Factor II was measured by a standard coagulation assay, by activation with E. carinatus venom, and by rocket immunoelectrophoresis. When sodium salicylate 5 mg or 25 mg was added to the liver perfusate (volume 100 ml) at the outset of the perfusion, cumulative synthesis of both coagulation activity and immunoreactive protein was significantly less than that seen in control perfusions containing no salicylate. The inhibitory effect of salicylate was prevented by pretreatment of rat liver donors with supplemental vitamin K injected 24 hours before sacrifice. Although some interaction between salicylate and vitamin K was apparent from these experiments, the results from vitamin K-deficient rat liver donors were quite different from those containing salicylate. There was no assayable Factor II coagulation activity produced in 10 hours of perfusion of vitamin K-deficient rat livers, but cumulative synthesis of immunoreactive Factor II was quite comparable to that seen in control perfusions.

Animals↗

PubMed2002

PCR-cloning and gene expression studies in common carp (Cyprinus carpio) insulin-like growth factor-II.

Insulin-like growth factor-II (IGF-II) is a member of a growth factor family related to fetal growth in mammals but its physiological role has not been clearly identified in fish. In teleosts, the basic mechanism of the growth hormone (GH)-IGF axis is known to be operative but in a different manner. For instance, IGF-I exhibits GH dependence whereas for IGF-II, its GH dependence varies in different fish species. In this study, we used polymerase chain reaction (PCR) to obtain a common carp IGF-II (ccIGF-II) cDNA fragment and methods of rapid amplification of cDNA ends (RACEs) to obtain a full-length ccIGF-II sequence. The ccIGF-II encodes for a predicted amino acid sequence showing identities of 70.6%, 68.7%, 63.4% and 35% in comparison with salmon, barramundi, tilapia and human IGF-II, respectively. The nucleotide identity between the open reading frame (ORF) of the ccIGF-II and ccIGF-I cDNA sequence is only 36.2%. Distribution of ccIGF-II mRNA levels in common carp tissues was also studied; ccIGF-II expressed in hepatopancreas, heart, and many other tissues in adult carps are similar to the levels of ccIGF-I except in gills and testis. ccIGF-II levels were significantly higher than that of ccIGF-I in most juvenile tissues except in hepatopancreas, where ccIGF-I was higher (threefold) than that of ccIGF-II. The levels of ccIGF-I were also higher than ccIGF-II in carp larvae, from pre-hatched stage to day 30 post-hatching. Injection of porcine GH (pGH) increased the IGF-I and IGF-II mRNA levels in the hepatopancreas and brain of juvenile carps. However, hepatic IGF-I mRNA levels were induced more than IGF-II by pGH, whereas ccIGF-II levels gave a higher response than IGF-I in the brain in response to GH induction.

Amino Acid Sequence↗

PubMed1997

A functional Sp1 binding site is essential for the activity of the adult liver-specific human insulin-like growth factor II promoter.

The human gene encoding insulin-like growth factor II contains four promoters (P1-P4) that are differentially activated in various tissues during development. Expression of insulin-like growth factor II in adult liver tissue is directed by P1, which is activated by liver-enriched members of the CCAAT/enhancer binding protein family of transcription factors. In the present report we show that the region around -48 relative to the transcription start site contains a high affinity Sp1 binding site. This was demonstrated by electrophoretic mobility shift assays using nuclear extracts from Hep3B hepatoma cells and with specific antibodies directed against Sp1. Competition electrophoretic mobility shift assays revealed that the Sp1 binding site of P1 and a consensus Sp1 binding site bind Sp1 with comparable efficiencies. Mutation of the Sp1 binding site results in an 85% decrease in P1 promoter activity in transient transfection assays using two different cell lines, COS-7 and Hep3B. Investigation of P1 mutants in which the spacing of the Sp1 binding site and the transcription start site was increased showed that the role of the Sp1 binding site in regulation of P1 is position dependent. Interestingly, the Sp1-responsive element cannot be exchanged by a functional TATA box. Activation of P1 by transactivators CCAAT/enhancer binding protein-beta and hepatocyte nuclear factor-3beta is strongly impaired after mutation of the Sp1 binding site. These results demonstrate that the specific presence of a binding site for the ubiquitously expressed transcription factor Sp1 is of eminent importance for efficient activation of P1 by liver-enriched transactivators.

Age Factors↗

PubMed1994

A guanosine quadruplex and two stable hairpins flank a major cleavage site in insulin-like growth factor II mRNA.

Insulin-like growth factor II (IGF-II) mRNAs are cleaved by an endonucleolytic event in a conserved part of their 3' untranslated region that is predicted to exhibit a complex higher-order RNA structure. In the present study, we have examined the putative secondary structures of in vitro transcripts from the conserved part of human and rat mRNAs by enzymatic and chemical probing. The results show that the cleavage site is situated between two highly structured domains. The upstream domain consists of two large hairpins, whereas the downstream domain is guanosine-rich. The guanosine-rich domain adopts a compact unimolecular conformation in Na+ or K+ but not in Li+, and it completely arrests reverse transcription in K+ but only partially in Na+, indicating the presence of an intramolecular guanosine quadruplex. The flanking higher-order structures may ensure that the cleavage site is not sequestered in stable RNA structures, thus allowing interactions with RNA or proteins at posttranscriptional stages of IGF-II expression.

Animals↗

PubMed1978

The absence of factor II in a child with systemic lupus erythematosus.

This report describes a patient with active system lupus erythematosus (SLE), who developed haemorrhagic diathesis due to a lowering of plasma factor II activity. No evidence was found suggesting a plasma inhibitor of factor II. The present case indicates that in some patients with SLE, factor II activity may be low or completely absent due to impairment of factor II synthesis, further that prednisone, but not azathioprine, may ameliorate this defect.

Child↗

PubMed1985

Chemical synthesis of insulin-like growth factor II.

Human insulin-like growth factor II (IGF-II) with 67 amino acids and three disulfide bridges has been synthesized by the solid-phase method. The synthetic hormone is shown to be homogeneous in high performance liquid chromatography (HPLC), high performance partition chromatography (HPPC), and chromatofocusing. It is indistinguishable from natural hormone in HPLC, peptide map of thermolysin digests, amino acid composition and radioreceptor binding assay. Thus, synthetic and natural IGF-II are identical.

Amino Acid Sequence↗

PubMed1994

Malignant rhabdoid tumor of the kidney expresses insulin-like growth factor II transcripts.

Insulin-like growth factor II (IGF-II) is thought to play a major role in fetal growth and development. High levels have been demonstrated in blastemal cells of both normal fetal kidney and Wilms' Tumor (WT). In this report, 2 cases of malignant rhabdoid tumor of the kidney (MRTK) were studied to detect the expression of IGF-II mRNA by in situ hybridization using 35S labelled RNA riboprobes. Results showed highly strong and specific IGF-II mRNA expression by tumor cells.

Child↗

PubMed1990

A growth-deficiency phenotype in heterozygous mice carrying an insulin-like growth factor II gene disrupted by targeting.

Growth factors are thought to function as pivotal autocrine-paracrine regulatory signals during embryonic development. Insulin-like growth factor II (IGF-II), a mitogenic polypeptide for a variety of cell lines, could have such a role, as indicated by the pattern of expression of its gene during rodent development. The IGF-II gene uses at least three promoters and expresses several transcripts in many tissues during the embryonic and neonatal periods, whereas expression in adult animals is confined to the choroid plexus and the leptomeninges. To examine the developmental role of IGF-II, we have begun to study the consequences of introducing mutations at the IGF-II gene locus in the mouse germ line. We have disrupted one of the IGF-II alleles in cultured mouse embryonic stem (ES) cells by gene targeting and constructed chimaeric animals. Germ-line transmission of the inactivated IGF-II gene from male chimaeras yielded heterozygous progeny that were smaller than their ES cell-derived wild-type littermates (about 60% of normal body weight). These growth-deficient animals were otherwise apparently normal and fertile. The effect of the mutation was exerted during the embryonic period. These results provide the first direct evidence for a physiological role of IGF-II in embryonic growth.

Animals↗

PubMed2002

Complete nucleotide sequence of the chum salmon insulin-like growth factor II gene.

Insulin-like growth factor II (IGF-II) is thought to play an important role in development and growth of vertebrates. In contrast to mammals, the IGF-II gene is expressed at a high level from the early stages of embryonic development until the adult stage and IGF-II peptide is produced in virtually all organs of bony fish, indicating a physiological importance of IGF-II 'under water'. Therefore, we describe here the complete nucleotide sequence (accession no. X97225) and organization of the chum salmon IGF-II gene. In addition, the phylogenetic relationship of the IGF-II hormones is analysed. Although the chum salmon contains two non-allelic insulin and IGF-I genes, only one IGF-II gene could be identified. The chum salmon IGF-II gene consists of four exons and is comprised of 7992 bp from the putative transcription initiation site to the poly(A) site. Activation of the only promoter of the salmon IGF-II gene gives rise to a single 4 kb transcript. The fish IGF-II gene is much smaller and simpler organized than its known mammalian counterparts that are governed by several tissue-specific and developmental stage-dependent promoters. All known mammalian IGF-II genes to date have been found to form a conserved linkage group with the insulin and tyrosine hydroxylase (TH) genes and are organized as TH-insulin-IGF-II genomic locus. However, in our study we could find no linkage between the insulin and IGF-II genes, or between the insulin, TH and IGF-II genes, at least within approximately 20 kb of the chum salmon IGF-II genomic sequence. In spite of minor differences, the overall organization of the IGF-II genes turned out to be very similar in bony fish. A limited analysis of the phylogenetic relationship between IGF-II prohormones indeed showed a very conservative phylogenesis of IGF-II in bony fish that may indicate the particular significance of IGF-II in these animals.

3' Untranslated Regions↗

PubMed1993

Expression, purification and binding to the receptor of human insulin-like growth factor II.

Human insulin-like growth factor II (IGF-II) was expressed as a fused protein with 14 additive amino acids in Escherichia coli with a high yield by an expression system using T7 RNA polymerase. Purification of the expressed protein was simply performed using only differential ultrafiltrations, giving a homogeneous preparation upon polyacrylamide gel electrophoresis and high-performance liquid chromatography. The expressed peptide was reacted with a monoclonal antibody raised against native IGF-II on a blotted membrane. Furthermore, the peptide was bound to IGF-II receptor in solubilized rat fetus membrane, though the affinity was slightly inferior to that of native IGF-II. In addition, fusion IGF-II immobilized on a gel matrix was useful for one-step purification of the IGF-II receptor with a high yield from solubilized rat fetus membranes.

Amino Acid Sequence↗

PubMed1994

Solution structure of human insulin-like growth factor II; recognition sites for receptors and binding proteins.

The three-dimensional structure of human insulin-like growth factor II was determined at high resolution in aqueous solution by NMR and simulated annealing based calculations. The structure is quite similar to those of insulin and insulin-like growth factor I, which consists of an alpha-helix followed by a turn and a strand in the B-region and two antiparallel alpha-helices in the A-region. However, the regions of Ala1-Glu6, Pro31-Arg40 and Thr62-Glu67 are not well-defined for lack of distance constraints, possibly due to motional flexibility. Based on the resultant structure and the results of structure-activity relationships, we propose the interaction sites of insulin-like growth factor II with the type 2 insulin-like growth factor receptor and the insulin-like growth factor binding proteins. These sites partially overlap with each other at the opposite side of the putative binding surface to the insulin receptor and the type 1 insulin-like growth factor receptor. We also discuss the interaction modes of insulin-like growth factor II with the insulin receptor and the type 1 insulin-like growth factor receptor.

Amino Acid Sequence↗

PubMed1988

Synthesis of insulin-like growth factor II (IGF-II) in fetal rat tissues: translation of IGF-II ribonucleic acid and processing of pre-pro-IGF-II.

The single insulin-like growth factor II (IGF-II) gene is transcribed into multiple RNA species in most fetal and neonatal rat tissues. For IGF-II to serve as a local growth factor in fetal tissues, IGF-II RNA must be translated into pre-pro-rat (r) IGF-II, and the biosynthetic precursor processed to smaller biologically active forms. IGF-II RNA extracted from fetal rat liver, muscle, intestine, lung, and stomach, from rat placenta, and from fetal or neonatal mouse liver and lung directed the synthesis of 22,000 mol wt pre-pro-IGF-II in a reticulocyte lysate cell-free translation system. A biosynthetic precursor of this size had been observed previously in translation of RNA from BRL-3A rat liver cells and is predicted by the nucleotide sequence of cDNA clones encoding rIGF-II. Consistent with the developmental pattern of expression of IGF-II RNA observed in hybridization studies, RNA from adult rat liver, muscle, and intestine did not direct the synthesis of pre-pro-rIGF-II. To determine whether the IGF-II biosynthetic precursor was processed to smaller biologically active IGF-II, term fetal rat tissues were extracted with acid-ethanol, the extracts were fractionated by acid gel filtration, and the IGF pools were examined in a RIA specific for IGF-II. Levels of 1-2 micrograms/g were observed in liver, limb, lung, intestine, and brain; lower levels were observed in heart and kidney. In general, the levels of immunoreactive IGF-II corresponded to the levels of IGF-II mRNA. These results suggest that IGF-II mRNA is translated, and pre-pro-IGF-II processed to mature IGF-II in different fetal rat tissues. In contrast to IGF-I, in which alternative RNA splicing generates possible precursor molecules containing different COOH-terminal propeptide segments, we find no evidence for an IGF-II precursor in rat tissues other than 22,000 mol wt pre-pro-rIGF-II.

Animals↗

PubMed1993

Insulin-like growth factor-II in human fetal adrenals: regulation by ACTH, protein kinase C and growth factors.

Insulin-like growth factor-II (IGF-II) may be one of the most important local growth factors in human fetal adrenals (HFAs), where its mRNA levels are upregulated by ACTH. We have investigated whether protein kinase C (PKC)-dependent mechanisms and various polypeptide growth factors participate in the regulation of IGF-II gene expression in cultured HFA cells, and whether HFA cells secrete IGF-II peptide into the culture medium. ACTH enhanced IGF-II mRNA accumulation dose- and time-dependently, maximally four- to sixfold, and this increase was inhibited dose-dependently (0.01-100 micrograms/l) by 12-O-tetradecanoyl phorbol-13-acetate (TPA), a PKC activator. TPA decreased basal IGF-II mRNA levels by approximately 55%. Staurosporine, a PKC inhibitor, abolished the inhibitory effects of TPA and induced accumulation of IGF-II mRNA. Dibutyryl cyclic AMP, cholera toxin and forskolin increased IGF-II mRNA accumulation as much as ACTH, and TPA inhibited these stimulations in a similar way. ACTH increased the IGF-II peptide concentration in most experiments, but this increase was modest in comparison with IGF-II mRNA changes. TPA, although it decreased IGF-II mRNA levels, tended to increase IGF-II peptide in the medium. Additions of GH, IGF-I and IGF-II to the cell culture medium also increased IGF-II mRNA accumulation. Transforming growth factor-beta 1 inhibited IGF-II mRNA accumulation to the same extent as TPA. Epidermal growth factor and basic fibroblast growth factor did not change IGF-II mRNA levels. Our results confirm previous reports that ACTH is an important regulator of IGF-II in human fetal adrenals, and show that IGF-II gene expression is under multifactorial control, which includes the PKC system and polypeptide growth factors.

Adrenal Glands↗

PubMed2004

Effects of insulin-like growth factor-II on the mitogenic and metabolic activities of equine articular cartilage with and without interleukin 1-beta.

OBJECTIVE: To investigate the effects of insulin-like growth factor-II (IGF-II) on DNA and glycosaminoglycan (GAG) synthesis and the expression of matrix-related genes in equine articular cartilage explants and chondrocytes, respectively, with and without interleukin 1-beta (IL1-beta). SAMPLE POPULATION: Articular cartilage from 12 adult horses. PROCEDURE: Articular cartilage was incubated in standard media with and without equine IL1-beta (10 ng/mL) containing various concentrations of IGF-II for 72 hours. Synthesis of DNA and GAG was determined by incorporation of thymidine labeled with radioactive hydrogen (3H) and sulfate labeled with radioactive sulfur (35S), respectively. Total GAG content of the explants and spent media was determined by use of the 1,9-dimethylmethylene blue assay. Northern blots of RNA from cultured equine articular cartilage chondrocytes were hybridized with cDNA of major matrix molecules. RESULTS: Insulin-like growth factor-II stimulated DNA and GAG synthesis at concentrations of 25 and 50 ng/mL, respectively. In cartilage explants conditioned with IL1-beta, IGF-II stimulated DNA and GAG synthesis at concentrations of 500 and 50 ng/mL, respectively. Insulin-like growth factor-II had no effect on total GAG content as determined by the 1,9-dimethylmethylene blue assay. No specific effects on steady-state levels of messenger RNAs were observed. CONCLUSIONS AND CLINICAL RELEVANCE: Insulin-like growth factor-II stimulated DNA and GAG synthesis in equine adult cartilage and may have potential application in vivo.

Analysis of Variance↗

PubMed2004

Mapping of the insulin-like growth factor II binding site of the Type I insulin-like growth factor receptor by alanine scanning mutagenesis.

The Type I insulin-like growth factor receptor is a physiological receptor for insulin-like growth factor II (IGF-II). To characterize the molecular basis of the receptor's ligand binding properties, we have examined the effects of alanine mutations of residues in the ligand binding site of the receptor on its affinity for IGF-II. The functional epitope for IGF-II comprises residues in the N-terminal L1 domain and residues at the C-terminus of the alpha subunit. Cysteine rich domain residues do not appear to be critical for IGF-II binding.

Alanine↗

PubMed1999

Mannose 6-Phosphate/Insulin-like growth factor II receptor mediates internalization and degradation of leukemia inhibitory factor but not signal transduction.

Leukemia inhibitory factor (LIF) is a multifunctional cytokine belonging to the interleukin-6 subfamily of helical cytokines, all of which use the glycoprotein (gp) 130 subunit for signal transduction. The specific receptor for LIF, gp190, binds this cytokine with low affinity and is also required for signal transduction. We have recently reported that glycosylated LIF produced by transfected Chinese hamster ovary cells also binds to a lectin-like receptor, mannose 6-phosphate/insulin-like growth factor II receptor (Man-6-P/IGFII-R) (Blanchard, F., Raher, S., Duplomb, L., Vusio, P., Pitard, V., Taupin, J. L., Moreau, J. F., Hoflack, B., Minvielle, S., Jacques, Y., and Godard, A. (1998) J. Biol. Chem. 273, 20886-20893). The present study shows that (i) mannose 6-phosphate-containing LIF is naturally produced by a number of normal and tumor cell lines; (ii) other cytokines in the interleukin-6 family do not bind to Man-6-P/IGFII-R; and (iii) another unrelated cytokine, macrophage-colony-stimulating factor, is also able to bind to Man-6-P/IGFII-R in a mannose 6-phosphate-sensitive manner. No functional effects or signal transductions mediated by this lectin-like receptor were observed in various biological assays after LIF binding, and mannose 6-phosphate-containing LIF was as active as non-glycosylated LIF. However, mannose 6-phosphate-sensitive LIF binding resulted in rapid internalization and degradation of the cytokine on numerous cell lines, which suggests that Man-6-P/IGFII-R plays an important role in regulating the amounts of LIF available in vivo.

3T3 Cells↗