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PubMed1992

The molecular and cellular biology of insulin-like growth factor II.

Insulin-like growth factor II (IGF-II) is a 67 amino acid polypeptide that belongs to the family of insulin-like peptides. The IGF-II gene is coupled to the insulin gene and paternally imprinted. Multiple IGF-II mRNAs with identical coding regions and 3' untranslated regions (UTRs) but different 5' UTRs are generated from 3 promoters. The transcripts are translationally discriminated and inactivated by a specific endonucleolytic cleavage in their 3' UTR. These features may be important in the control of IGF-II production. IGF-II functions in an auto- and paracrine manner and binds to two types of receptors. The IGF-I receptor that is a tyrosine kinase and closely related with the insulin receptor and the IGF-II/mannose 6-phosphate (IGF-II/Man 6-P) receptor that is identical with the cation-independent mannose 6-phosphate receptor. The mitogenic and metabolic actions of IGF-II are propagated by the IGF-I receptor. In contrast, the IGF-II/Man 6-P receptor, that target lysosomal enzymes from the Golgi apparatus or the plasma membrane to the lysosomes, mediates the rapid internalization and degradation of IGF-II. IGF-II is expressed at high levels during foetal life and it is a major growth factor for the foetus in rodents. The developmental profiles and tissue distribution of the IGF-I and the maternally imprinted IGF-II/Man 6-P receptors both parallel that of IGF-II. In this scenario IGF-II promotes the growth of the embryo through the IGF-I receptor, whereas the IGF-II/Man 6-P receptor balance the activity by controlling the extracellular level of IGF-II.

Amino Acid Sequence↗

PubMed1987

Factor II, VII, IX and X concentrations in patients receiving long term warfarin.

Using standard one stage clotting assays the concentrations of factors II, VII, IX and X were determined in 37 patients stabilised on warfarin for between three months and 17 years. Contrary to popular belief, the concentrations were not equally depressed, with factor X the lowest, factor II at intermediate value, factors VII and IX the highest. Some 71% of the variance of the British corrected ratio (BCR) could be accounted for by measurement of the factors assayed. Analysis of this variance showed 91% of the explained variance attributable to factor II, 7% to factor VII, 1.6% to factor IX and 0.4% to factor X. With the sudden and recent withdrawal of human thromboplastin, investigation of the sensitivities of the animal thromboplastins to changes in vitamin K dependent factors in orally anticoagulated patients is needed to ensure that the potentially alarming falls in factors II and X in these patients are being adequately detected.

Adult↗

PubMed1991

Modulation of insulin-like growth factor-II/mannose 6-phosphate receptors and transforming growth factor-beta 1 during liver regeneration.

Transforming growth factor-beta 1 (TGF-beta 1) is a potent mito-inhibiting substance that is thought to play an important function in regulating hepatocyte proliferation during liver regeneration. In this investigation, we have shown by immunohistochemistry that hepatocytes containing significant intracellular concentrations of TGF-beta 1 12 h after a two-thirds partial hepatectomy. This increase in hepatocyte TGF-beta 1 concentration was initially confined to those cells that resided in the periportal region of the liver. The elevation of intracellular TGF-beta 1 was, however, transient, and within 36 h, the hepatocytes positive for TGF-beta 1 had changed in a wavelike fashion from the periportal to the pericentral region of the liver lobules. By 48 h, most hepatocytes no longer contained TGF-beta 1. Interestingly, this temporary increase in TGF-beta 1 always preceded the onset of hepatocyte replication by approximately 3-6 h. Since TGF-beta 1 mRNA has been shown to be absent from hepatocytes normally and throughout liver regeneration, these results imply that the increase in intracellular TGF-beta 1 resulted from an augmented uptake. We have further shown that the insulin-like growth factor-II/mannose 6-phosphate (IGF-II/Man-6-P) receptors were up-regulated during liver regeneration and that the increased expression of this receptor co-localized in those hepatocytes containing elevated concentrations of TGF-beta 1. The latent TGF-beta 1 phosphomannosyl glycoprotein complex has been shown to bind to the IGF-II/Man-6-P receptor. Therefore, our data are consistent with the hypothesis that this latent complex is internalized through the IGF-II/Man-6-P receptor to the intracellular acidic prelysosomal/endosomal compartments where the mature TGF-beta 1 molecule could be activated by dissociation from the latent complex.

Animals↗

PubMed2003

The role of insulin-like growth factor II and its receptor in mouse preimplantation development.

Insulin-like growth factor II (IGF-II) and its receptor, the IGF-II/mannose-6-phosphate (IGF-II/M6P) receptor, are first expressed from the zygotic genome at the two-cell stage of mouse development. However, their role is not clearly defined. Insulin-like growth factor II is believed to mediate growth through the heterologous type 1 IGF and insulin receptors, whereas the IGF-II/M6P receptor is believed to act as a negative regulator of somatic growth by limiting the availability of excess levels of IGF-II. These studies demonstrate that IGF-II does have a role in growth regulation in the early embryo through the IGF-II/M6P receptor. Insulin-like growth factor II stimulated cleavage rate in two-cell embryos in vitro. Moreover, this receptor is required for the glycaemic response of two-cell embryos to IGF-II and for normal progression of early embryos to the blastocyst stage. Improved development of embryos in crowded culture supports the concept of an endogenous embryonic paracrine activity that enhances cell proliferation. These responses indicate that the IGF-II/M6P receptor is functional and likely to participate in such a regulatory circuit. The functional role of IGF-II and its receptor is discussed with reference to regulation of early development.

Animals↗

PubMed2004

Differential regulation of the insulin-like growth factor II mRNA-binding protein genes by architectural transcription factor HMGA2.

The developmentally regulated architectural transcription factor, high mobility group A2 (HMGA2), is involved in growth regulation and plays an important role in embryogenesis and tumorigenesis. Little is known, however, about its downstream targets. We performed a search for genes of which expression is strongly altered during embryonic development in two HMGA2-deficient mouse strains, which display a pygmy-phenotype, as compared to wild-type mice. We found that the insulin-like growth factor II mRNA-binding protein 2 gene (IMP2), but not its family members IMP1 and IMP3, was robustly downregulated in mutant E12.5 embryos. Furthermore, we show that wild-type HMGA2 and its tumor-specific truncated form have opposite effects on IMP2 expression. Our results clearly indicate that HMGA2 differentially regulates expression of IMP family members during embryogenesis.

Amino Acid Sequence↗

PubMed1990

Inappropriately elevated plasma insulin-like growth factor II in relation to suppressed insulin-like growth factor I in the diagnosis of non-islet cell tumour hypoglycaemia.

The diagnosis of non-islet cell tumour (hypoinsulinaemic) hypoglycamia has been complicated by contradictory biochemical evidence. Although insulin-like growth factor II (IGF-II) has been identified as the hypoglycaemic agent, plasma levels are often not elevated. In this study specific radioimmunoassay procedures for the measurement of IGF-I and IGF-II are described. Reference data on plasma IGF-II concentrations in relation to a wide range of IGF-I levels have been accumulated using plasma samples from acromegalic, hypopituitary and insulinoma (i.e. hyperinsulinaemic hypoglycaemia) patients as well as normal subjects from all age groups. The reference data indicate that a low plasma IGF-I value is normally associated with a relatively low plasma IGF-II level. Within a group of hypoinsulinaemic hypoglycaemia patients, a small number, invariably with evidence of a neoplasm, had low plasma IGF-I concentrations but apparently normal IGF-II levels. We propose that, in such cases, an apparently normal plasma IGF-II value is inappropriately high for the low plasma IGF-I level and, in association with non-ketotic hypoinsulinaemia and suppressed plasma growth hormone (GH), is diagnostic of a non-islet cell tumour as the cause of hypoglycaemia.

Adult↗

PubMed1996

Discordant Regulation of insulin-like growth factor-II and insulin-like growth factor binding protein-2 gene expression in a rat beta-cell line.

Expression and regulation of IGFBP-2 and IGF-II by GH and glucose in the rat insulin producing beta-cell line, INS-1, were determined. These cells express high levels of the insulin-like growth factor II (IGF-II) gene which is regulated by glucose. GH has no regulatory activities on IGF-II or IGFBP-2 gene expression. The levels of IGF-II and IGFBP-2 mRNA at increasing glucose concentrations are inversely regulated and exogenously added insulin inhibits IGFBP-2 gene expression at low glucose. These observations suggest that the expression of IGFBP-2 gene in this cell line is under the negative control of the endogenously produced insulin (and/or IGF-II) which accumulates to effective levels in the medium when the cells are cultured at high glucose concentrations.

Animals↗

PubMed2000

Binding of 125I-insulin-like growth factor-II to cells cultured in fetal bovine serum: a complication.

Insulin-like growth factor II is an important fetal mitogen in mice and humans and its biological activity is regulated in a complex manner. The peptide interacts with three membrane-bound receptors, with a superfamily of insulin-like growth factor binding proteins and with the proteoglycan, glypican-3. Recently, the blood protein, vitronectin, has been identified as a novel insulin-like growth factor II-binding protein. Many studies have used cell lines maintained in fetal bovine serum to identify cell surface insulin-like growth factor II binding sites. We now describe a complication associated with the interpretation of such in vitro studies. Fetal bovine serum-derived vitronectin adheres very tightly to tissue culture dishes. When cells that have been maintained in fetal bovine serum are incubated with 125I-insulin-like growth factor II, a substantial fraction of the 125I-insulin-like growth factor II apparently associated with the cell surfaces may represent radioliogand bound by the fetal bovine serum-derived vitronectin. This may result in over-estimation of cell surface insulin-like growth factor II binding sites.

Animals↗

PubMed1989

The relative importance of the factors II, VII, IX and X for the prothrombinase activity in plasma of orally anticoagulated patients.

The individual importance of each of the four vitamin K-dependent clotting factors on the generation of prothrombinase activity in the plasma of orally anticoagulated patients has been investigated. Addition of purified factors VII, IX or X to plasma from deeply anticoagulated patients (International Normalized Ratio 2.8-4.8) did not influence the amount of prothrombinase activity or the amount of thrombin formed. Only the prothrombin level in the plasma determines the course of thrombin generation. Addition of increasing amounts of purified factor II, VII, IX or X to plasmas deficient in respectively factor II, VII, IX or X showed that the prothrombinase activity increases linearly with the concentration of factor II added and that the concentration below which the factors VII, IX and X start to have a measurable effect on prothrombinase activity are 5%, 20%, and 30%, respectively. Half maximal prothrombinase activity was found at about 1% factor VII, 5% factor IX and 8% factor X respectively. From these observations we conclude that primarily the variation in factor II level determines thrombin generation and hence presumably the antithrombotic effect of oral anticoagulant therapy. It therefore seems likely that, for the control of oral anticoagulant therapy, tests that reflect factor II activity would be suitable.

Administration, Oral↗

PubMed1976

Post-natal development of factor II (pre-prothrombin and prothrombin) in man.

Postnatal development of factor II molecule has been evaluated by three different methods in infants and children from 15 days to 7 years of age. The immunochemical determination of factor II showed that the plasma levels of this factor reached the lowest adult values between 4-7 months of age and rose slowly for all the first year; after this age the plasma concentration was steady. The adult range was reached from 15 to 120 days of age when the factor II was evaluated by the method of Owren and Aas (19) and by staphylocoagulase reagent.

Age Factors↗

PubMed1999

A common polymorphism in exon 40 of the human mannose 6-phosphate/insulin-like growth factor II receptor gene.

Mammalian mannose 6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) binds insulin-like growth factor II and ligands containing an M6P recognition marker like the latent transforming growth factor-beta. Its genetic alteration has been associated with tumorigenesis of various tumours. We report here a novel polymorphism in exon 40 of the human M6P/IGF2R gene (6206A-->G, Asn2020Ser). The G allele frequency was 0.347 in Japanese. Observed heterozygosity was 0.468. The polymorphism may be useful for studying loss of heterozygosity in primary tumours and gene imprinting.

Chromosome Mapping↗

PubMed1994

[Activity of coagulation factors II, V, VII and X in healthy dogs--dependence on age, sex and breed].

The activity of the coagulation factors II, V, VII and X was measured in plasmas of 167 healthy dogs of different age, sex and breeds using a test optimized for dogs. During the first months of life particularly the factor X-activity, but also the activity of factor-II-, and by way of suggestion the factor V-activity was lower in comparison to adult dogs. A dependence on the sex was only seen for the factor II- (p = 0.0497) and V-activity (p = 0.0467), which was slightly higher in not castrated female than in male dogs. Significant differences between different breeds existed for factor VII. With regard to a collective of different breeds the reference values (2.5- and 97.5%-quantile) were calculated for adult dogs (n = 111). Especially the range of the factor VII- (62-180%), and also of factor V-activity (68-137%) was wider than that of the factor II- (84-126%) and factor X-activity (77-121%).

Aging↗

PubMed1992

Acute actions of insulin-like growth factor II on glucose metabolism in adult rats.

The metabolic potency of recombinant human insulin-like growth factor II was studied in anaesthetized adult rats by obtaining dose-response curves for the hypoglycaemic action and for the stimulation of glucose metabolism during euglycaemic clamping. Compared to insulin, about 50 times higher doses of insulin-like growth factor II were required to result in identical in vivo responses, with half-maximally effective serum concentrations for the stimulation of glucose disposal during clamp studies of about 0.8 and 50 pmol/ml, respectively. A similar difference in potency was observed for the dose-dependent stimulatory actions on glucose metabolism in individual target tissues. Half-maximally effective serum concentrations in the range of 0.8 to 3.0 pmol/ml for insulin and of 40 to 70 pmol/ml for insulin-like growth factor II were seen to be required for 2-deoxyglucose uptake, glycogen formation in skeletal muscle and lipogenesis in epididymal fat. Maximal responses were identical with both peptides. These data suggest that in vivo acute metabolic actions of insulin-like growth factor II on carbohydrate metabolism occurred through insulin receptors.

Animals↗

PubMedDate not supplied

Polymorphisms in the genes for coagulation factor II, V, VII in patients undergoing coronary angiography.

OBJECTIVE: To determine whether polymorphisms in the genes for coagulation factor II, V, VII could predispose an individual to increase risk for coronary artery disease (CAD) and/or myocardial infarction (MI) in Chinese. METHODS: We screened coagulation factor II(G20210A),V(G1691A),VII (R353Q and HVR4) genotype in 374 patients undergoing coronary angiography by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) assay. RESULTS: The R353Q and HVR4 genotype of the factor VII distribution was in accordance with Hardy-Weinberg equilibrium. The frequencies of FVII genotype or allele did not show statistically significant differences between CAD group and controls or between male and female. The frequencies of the Q allele and (RQ + QQ) genotype were significantly higher among the CAD patients without myocardial infarction (MI) history than among those with MI history (P < 0.05). However, HVR4 polymorphism was not significantly different within groups. We only find one normal control of factor II (G20210A) mutation. No coagulation factor V(G1691A) mutation was found in the CAD patients and controls. CONCLUSION: The factor II(G20210A) ,V(G1691A) mutation is absent and may not be a major genetic factor for CAD and/or MI; the Q allele of the R353Q polymorphism of the factor VII gene may be a protective genetic factor against myocardial infarction in Chinese.

China↗

PubMed2005

Stability of frozen serum levels of insulin-like growth factor-I, insulin-like growth factor-II, insulin-like growth factor binding protein-3, transforming growth factor beta, soluble Fas, and superoxide dismutase activity for the JACC study.

BACKGROUND: Subjects of the Japan Collaborate Cohort Study (JACC Study) gave peripheral blood samples collected between 1988 and 1990. We conducted to investigate whether levels of serum components measured after 9 years of frozen storage are stable or not. METHODS: To assess the degradation of frozen serum components in the JACC Study, we compared levels of various components (IGF-I, IGF-II, IGFBP-3, TGF-beta 1, sFas, and total SOD activity) between fresh and stored sera collected from other inhabitants. Serum levels of constituents were measured by immunoradiometric assay (IGF-I, IGF-II and IGFBP-3), quantitative enzyme immunoassay (TGF-beta1), enzyme-linked immuno-adsorbent assay (sFas), and an improved nitrite method (SOD activity). RESULTS: The coefficients of variation for intra- and inter-assay precisions of the measurements were less than 9%. Levels of IGF-I, IGF-II, IGFBP-3, TGF-beta 1 and sFas in sera after storage for 9 years at--80 degrees C were similar to those of fresh sera newly collected from inhabitants. The distributions of serum IGF-I, IGF-II, IGFBP-3, TGF-beta 1, sFas and SOD activity for specimens collected from different individuals tended to be similar to those of serum levels for frozen specimens collected from different individuals and stored for 9 years. CONCLUSIONS: There was no statistically significant difference in distribution of measured values of IGF-I, IGF-II, IGFBP-3, TGF-beta 1, and sFas between newly collected sera and frozen specimens stored for 9 years. Thus, measurements of these serum constituents of specimens stored for the JACC Study can be reliably used in nested case-control study.

Adult↗

PubMedDate not supplied

Expression of insulin-like growth factor II in female breast cancer as related to established prognostic factors and long-term prognosis.

The expression of insulin-like growth factor II (IGF-II) was analysed immunohistochemically in a series of 211 breast cancers with special reference to standard prognostic factors and patient survival. IGF-II was expressed both in the cancer cells and in stromal cells, in 84% and 50% of cases, respectively. IGF-II expression in cancer cells was related to a non-metastatic disease at diagnosis (p = 0.03), low tumour grade (p = 0.02), DNA diploidy (p = 0.02) and S-phase fraction under 7% (p = 0.001). IGF-II negativity was positively correlated to morphometric SD of nuclear area (p = 0.0003), nuclear perimetry (p = 0.002), SD of nuclear perimetry (p = 0.02), minimum nuclear diameter (p = 0.005) and maximum nuclear diameter (p = 0.003). The expression of IGF-II in stromal cells was related to low histological grade (p = 0.02), mitotic index under 10/mm2 (p = 0.01), mild nuclear pleomorphism (p = 0.03), DNA diploidy (p = 0.08), SD of nuclear area (p = 0.006), mean nuclear perimeter (p = 0.05), minimum nuclear diameter (p = 0.005) and maximum nuclear diameter (p = 0.007) in that the nuclear factor values were higher in tumours without stromal IGF-II expression. In univariate and multivariate survival analysis, immunohisto-chemically detected expression of IGF-II had no independent prognostic value over standard prognostic factors. Despite the fact that expression of IGF-II was inversely related to several histopathological features of malignancy, the clinical behaviour of breast cancer seemed to be independent of IGF-II expression.

Adult↗

PubMed1997

Light-microscopic study of insulin like growth factor II (IGF-II) and insulin like growth factor I receptor (IGF-I-R) in myopathy.

The insulin like growth factors (IGFs) are mitogenic peptides that can stimulate cell division and differentiation. In experimental studies it has been shown that there is local-production of IGFs and their mRNA in regenerating muscle. The effect of IGF-I and -II is mediated by a cell surface, membrane bound receptor (IGF-I-R). In addition, IGF-II has its own distinct type 2 receptor. But the role of IGF-II binding to the type 2 receptor is unclear, and it is now widely believed that the growth-promoting activities of IGF-II are also mediated via the IGF-I-R. So far, there is some knowledge about the regulation and effects of IGFs in muscle regeneration in vitro and in animal models in vivo. However, cell lines and in vitro experiments with myogenic precursors differ in some respects from human regenerating muscle in vivo. Thus, we performed our immunohistochemical study to investigate the potential role of IGF-II and IGF-I-R in regenerating human skeletal muscle in situ. To investigate the state of regeneration, neural cell adhesion molecule (N-CAM) and cytoskeletal protein vimentin serial sections were also performed. Light-microscopic evaluation showed that muscle fiber regeneration in inflammatory and dystrophic myopathy corresponds closely to IGF-II and IGF-I-R immunoreactivity in muscle fibers. The coexpression of IGF-II and IGF-I-R in regenerating muscle fibers corroborates the assumption that in human skeletal muscle there is a trophic pathway concerning the synthesis and autocrine action of IGF-II via the IGF-I-R. In conclusion, in human skeletal muscle, in vivo, muscle fiber derived IGF-II probably is biologically active on the cell type of origin and may play an autocrine role in muscle regeneration via the IGF-I-R.

Biopsy↗

PubMed1987

Decrease in blood coagulation factors II (prothrombin), VII, IX and X in the rat after a single oral dose of butylated hydroxytoluene.

Male Sprague-Dawley rats were given butylated hydroxytoluene (BHT) in a dose of 800 mg/kg body weight orally, and 0.5-72 hr later plasma concentrations of factors II, VII, IX and X and hepatic levels of BHT and BHT quinone methide (2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone) were determined. Levels of factors II, VII, X and IX were reduced 36-60 hr after BHT treatment, but by 72 hr, those most affected (VII and IX) showed some recovery and X had returned to normal. Hepatic levels of BHT reached a maximum 3 hr (a major peak) and 24 hr after BHT dosing and BHT quinone methide reached a maximum at 6 and 24 hr (a major peak). In rats given BHT orally in doses of 200, 400 and 800 mg/kg, factors II, VII and X decreased after 48 hr only in rats given the highest dosage, but factor IX was more susceptible to BHT and showed a dose-dependent decrease. Phylloquinone (1 mg/rat) injected ip 24 hr after the administration of 800 mg BHT/kg maintained normal levels of factors VII and X and an almost normal level of factor IX, but had little effect on the level of factor II. In studies of the effects of drug-metabolizing-enzyme modifiers, neither ip pretreatment with 75 mg phenobarbital sodium/kg for 3 days nor the feeding of 1% cysteine in the diet throughout the experiment prevented the decrease in vitamin-K-dependent factors by 800 mg BHT/kg, but 2-day ip pretreatment with 60 mg cobaltous chloride/kg/day maintained normal levels of factors II and VII and reduced the BHT effect on factors IX and X. SKF 525A (50 mg/kg) injected ip either 30 min before or 12 hr after BHT treatment partially prevented the decrease in factors II, VII and X, or in all four factors, respectively. Thus the decrease in vitamin K-dependent factors may be the same with a single oral dose of BHT as with dietary BHT, and the anticoagulant effect may require the metabolic activation of BHT.

Animals↗