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PubMed1992

Type 1 IGF receptor in human breast diseases.

The first step of the action of IGF1 and IGF2 (IGFs) is their binding to membrane receptors. IGF binding sites have been characterized by competitive binding and cross-linking techniques in human breast cancer cell lines as well as in human breast cancers and in human benign breast diseases. IGF2 is a good competitor of 125I-IGF1 binding to IGF1-R; insulin competes but with a potency 1/100 lower than the IGF1 potency. Chemical cross-linking experiments revealed that the apparent molecular weight of the IGF1-binding sites is 130,000. Alpha IR-3, a murine monoclonal antibody against the IGF1-R, blocks IGF1-binding to this receptor. This antibody inhibits the IGF1-stimulated growth of breast cancer cells. Therefore, the IGF1 specific binding sites correspond to the previously described type 1 IGF receptors (IGF1-R) in normal tissues. Cross-linking experiments with labeled IGF2 resulted in a major band of apparent Mr 260,000-270,000 that was inhibited by unlabeled IGF2 but not by insulin, and corresponds to the type 2 IGF receptor; a second band of apparent Mr 130,000 was inhibited by excess IGFs and insulin (Type I receptor). The alpha-IR3 inhibition of the IGF2 mitogenic activity suggest that IGF1-R partially mediates the growth effect of IGF2 in these cells. We and others have demonstrated that most breast cancer cell lines contain IGF1-R.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast↗

PubMed2006

Paracrine release of insulin-like growth factor 1 from a bioengineered tissue stimulates skeletal muscle growth in vitro.

Bioengineered tissues transduced to secrete recombinant proteins may serve as a long-term delivery vehicle for therapeutic proteins when implanted in vivo. Insulin-like growth factor 1 (IGF1) is an anabolic growth factor for skeletal muscle that can stimulate myoblast proliferation and myofiber hypertrophy. To determine whether the release of IGF1 from an engineered bioartificial skeletal muscle (BAM) could stimulate the growth of skeletal muscle in a paracrine manner, we established an in vitro perfusion system for genetically engineered IGF1 BAMs. BAMs were bioengineered from C2C12 murine myoblasts stably transduced with a retroviral vector to synthesize and secrete IGF1 (C2-IGF1 BAMs). C2-IGF1 BAMs or nontransduced control C2 BAMs were cocultured with avian BAMS (ABAMs) in constantly perfused biochambers. During 11 days of perfusion, IGF1 levels in the C2-IGF1 BAM perfusion medium increased linearly from 1 to 20 ng/mL. The ABAMs maintained in biochambers with the C2-IGF1 BAMs had significantly more myofibers (69%, p < 0.005) and larger myofiber cross-sectional areas (40%, p < 0.001) compared to those cocultured with control C2 BAMs. These studies show that levels of IGF1 secreted from the C2-IGF1 BAMs are sufficient to produce an anabolic paracrine effect on nongenetically engineered BAMs, and the in vitro perfusion system provides a model for screening proteins effective in stimulating localized skeletal muscle growth.

Animals↗

PubMed1988

Insulin and insulin-like growth factor 1 receptors during postnatal development of rat brain.

The binding of insulin and insulin-like growth factor 1 (IGF1) to high-affinity sites in the brain of rats aged 2-37 days was studied. Specific binding of insulin and IGF1 was assessed using tracer concentrations of 125I-insulin or 125I-IGF1. Sites for insulin and IGF1 were distinguished in these conditions as shown by competition experiments. The Kd were 3.6 nM (insulin) and 2.0 nM (IGF1). These values did not change significantly over the age range studied. The numbers of high-affinity binding sites for insulin and IGF1 were similar in adult animals. IGF1 binding was higher than the insulin binding in 2-day-old animals. The binding capacity for both insulin and IGF1 decreased from birth to age 15 and days remained stable thereafter. Tyrosine kinase activity, which is associated with these receptors, was measured using the artificial substrate poly (Glu, Tyr). It decreased over the first 15 days of life and remained stable thereafter. Autophosphorylation of the receptors confirmed this result. This decrease appears to be due to changes in the numbers of the two types of receptors, and is probably a reflection mainly of the variation in the number of IGF1 receptors. Similar results for insulin and IGF1 binding as well as tyrosine kinase activity were obtained with hypothyroid rats.

Aging↗

PubMed1992

Insulin-like growth factor 1 receptors in human breast tumour: localisation and quantification by histo-autoradiographic analysis.

To assess the precise role of IGF1 in benign and malignant breast diseases, we analysed the tissular localisation, characterised, and quantified specific insulin-like growth factor 1 (IGF1) binding sites in these heterogenous tissues, using histo-autoradiographic analysis (HAA). The 125I-IGF1 binding was performed on frozen tissue sections and analysed using 3H Ultrofilm autoradiography coupled to computerised image analysis. Competitive binding experiments using unlabelled IGF1, IGF2 and insulin showed that the tissues exhibited typical type I IGF binding sites. This specificity was confirmed by the use of alpha IR-3 monoclonal antibody, as inhibitor of 125I-IGF1 binding. IGF1 binding sites were detected in 18 human primary breast cancers, 12 benign breast tumours and two normal breast tissues. Using HAA we found that the human breast carcinomas studied exhibit a specific and high binding capacity for 125I-IGF1 exclusively localised on the proliferative epithelial component. The 125I-IGF1 binding activity of benign breast tumours or normal breast tissue was significantly lower than in cancerous tissues. There was a significant correlation between IGF1-R concentrations detected with HAA and those detected with a classical biochemical method. Moreover, HAA could be useful in further detailing whether a tumour is IGF1-R positive or negative HAA appears to be a useful method for the detection of growth factor receptors, specially in small biopsy specimens.

Autoradiography↗

PubMed1990

Expression and characterization of an antibody binding specificity joined to insulin-like growth factor 1: potential applications for cellular targeting.

To create antibody molecules with improved functional properties, a growth factor (insulin-like growth factor 1, IGF1) was used to replace the constant region of a chimeric mouse-human IgG3 anti-dansyl antibody. The chimeric heavy chain was expressed with an anti-dansyl-specific chimeric kappa light chain. The IgG3-IGF1 chimeric protein retained its specificity for the antigen dansyl. The chimeric proteins bound to the IGF1 receptors of the human lymphoblast IM-9, albeit with reduced affinity, and elicited some of the same biologic effects (increased glucose and amino acid uptake) in human KB cells as did human IGF1, but with reduced specific activity. The reduced affinity and biologic activity may result from several things: the presence of the unprocessed IGF1 moiety, the large size of the IgG3-IGF1 chimeric protein (160 kDa) compared with IGF1 (7 kDa), and three amino acid substitutions in rat IGF1 compared with human IGF1, which may lead to decreased affinity for the human IGF1 receptor. The chimeric proteins show that it is feasible to produce a new family of immunotherapeutic molecules targeted to growth factor receptors.

Amino Acid Sequence↗

PubMed2002

Inhibition of apoptosis by amphiregulin via an insulin-like growth factor-1 receptor-dependent pathway in non-small cell lung cancer cell lines.

Several abnormalities in the insulin-like growth factor-1 (IGF1) and erbB receptors pathways stimulate the growth and survival of lung cancer cells, but their mechanisms of action and cooperation are poorly understood. In this report, we have identified a new mechanism of apoptosis inhibition by amphiregulin through an IGF1-dependent survival pathway in non-small cell lung cancer (NSCLC) cells: amphiregulin activates the IGF1 receptor that in turn induces the secretion of amphiregulin and IGF1. In the absence of serum, the NSCLC cell line H358 resists apoptosis and secretes factors protecting the NSCLC cell line H322 from serum deprivation apoptosis. IGF1 receptor inhibitor AG1024 as well as epidermal growth factor receptor inhibitors AG556 and ZD1839 restore apoptosis in H322 cells cultured in H358-conditioned medium. Accordingly, the anti-apoptotic activity of H358-conditioned medium is completely abolished after incubation with anti-amphiregulin neutralizing antibody and only partially with anti-IGF1 neutralizing antibody. H358-conditioned medium and amphiregulin induce IGF1 receptor phosphorylation in H322 cells, which is prevented by anti-amphiregulin neutralizing antibody but not by AG556 or ZD1839. H358 cells secrete a high level of amphiregulin that, in combination with IGF1, prevents serum deprivation apoptosis. Finally, IGF1 receptor inhibitor blocks amphiregulin and IGF1 release by H358 cells.

Amphiregulin↗

PubMed1988

Presence and characterization of insulin-like growth factor 1 receptors in human benign breast disease.

Insulin-like growth factor 1 binding sites were characterized in human benign breast disease. We demonstrated the presence of one high affinity binding site. Chemical cross-linking of [125I]IGF1 to benign breast disease membranes in reducing condition and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed one band with an apparent Mr of 130,000. The specificity of the binding was studied: IGF 2 was a good competitor whereas insulin competed for binding with a potency lower than 1/100 that of IGF1. This IGF1 binding corresponded to the previously described type I IGF receptor (IGF1-R). IGF1-R was assayed in 35 cases of benign breast disease and two samples of normal breast tissue. Forty-three per cent of the lesions were IGF1-R positive. The mean geometric level of specific binding was 1.98% in the whole population, it was significantly lower in adenofibromas (1.55%) than in epithelial hyperplasia (2.5%); it was 2% in dystrophic disease. IGF1-R was undetectable in normal tissue. Considering our previous results showing that almost all the breast cancers contained IGF1-R, these data suggest that the increase in IGF1-R could be a marker of malignant tumor development.

Adenofibroma↗

PubMed2000

Insulin-like growth factor 1 regulates developing brain glucose metabolism.

The brain has enormous anabolic needs during early postnatal development. This study presents multiple lines of evidence showing that endogenous brain insulin-like growth factor 1 (Igf1) serves an essential, insulin-like role in promoting neuronal glucose utilization and growth during this period. Brain 2-deoxy-d- [1-(14)C]glucose uptake parallels Igf1 expression in wild-type mice and is profoundly reduced in Igf1-/- mice, particularly in those structures where Igf1 is normally most highly expressed. 2-Deoxy-d- [1-(14)C]glucose is significantly reduced in synaptosomes prepared from Igf1-/- brains, and the deficit is corrected by inclusion of Igf1 in the incubation medium. The serine/threonine kinase Akt/PKB is a major target of insulin-signaling in the regulation of glucose transport via the facilitative glucose transporter (GLUT4) and glycogen synthesis in peripheral tissues. Phosphorylation of Akt and GLUT4 expression are reduced in Igf1-/- neurons. Phosphorylation of glycogen synthase kinase 3beta and glycogen accumulation also are reduced in Igf1-/- neurons. These data support the hypothesis that endogenous brain Igf1 serves an anabolic, insulin-like role in developing brain metabolism.

Animals↗

PubMed2005

Overexpression of des(1-3) insulin-like growth factor 1 in the mammary glands of transgenic mice delays the loss of milk production with prolonged lactation.

During prolonged lactation, the mammary gland gradually loses the capacity to produce milk. In agricultural species, this decline can be slowed by administration of exogenous growth hormone (GH), which is believed to act through insulin-like growth factor 1 (IGF1). Our previous work demonstrated delayed natural mammary gland involution in des(1-3)IGF1-overexpressing transgenic mice (Tg[Wap-des{1-3}IGF1]8266 Jmr), hereafter referred to as WAP-DES mice. The present study tested the hypothesis that overexpressed des(1-3)IGF1 would delay the loss of milk production during prolonged lactation. Accordingly, we examined lactational performance in WAP-DES mice by artificially prolonging lactation with continual litter cross-fostering. Over time, lactational capacity and mammary development declined in both WAP-DES and control mice. However, the rate of decline was 40% slower in WAP-DES mice. Mammary cell apoptosis increased by 3-fold in both groups during prolonged lactation but was not different between genotypes. Plasma concentrations of murine IGF1 were decreased in WAP-DES mice, while those of the transgenic human IGF1 were elevated during prolonged lactation. Phosphorylation of the mammary IGF1 receptor was increased in the WAP-DES mice, but only during prolonged lactation. Plasma prolactin decreased with prolonged lactation in nontransgenic mice but remained high in WAP-DES mice. The WAP-DES mice maintained a higher body mass and a greater lean body mass during prolonged lactation. These data support the conclusion that overexpressed des(1-3)IGF1 enhanced milk synthesis and mammary development during prolonged lactation through localized and direct activation of the mammary gland IGF1 receptor and through systemic effects on prolactin secretion and possibly nutrient balance.

Animals↗

PubMed2006

Insulin-like growth factor-1 genotype predicts breast volume after pregnancy and hormonal contraception and is associated with circulating insulin-like growth factor-1 levels: implications for risk of early-onset breast cancer in young women from hereditary breast cancer families.

BACKGROUND: BRCA1/2 mutations predispose to early-onset breast cancer, especially after oral contraceptive (OC) use and pregnancy. However, the majority of breast cancers might be due to more prevalent low penetrance genes that may also modify the risk in BRCA1/2 mutation carriers. The absence of the IGF1 19-CA repeat allele has been associated with high insulin-like growth factor-1 (IGF-1) levels during OC use in nulliparous women of four different ethnic groups. High IGF-1 levels are linked to an increased risk of early-onset breast cancer and to larger breast volumes in the general population. It has also been hypothesized that women whose breast size increases while exposed to OCs may be at increased risk of future breast cancer. AIM: We explored the effect of the IGF1 genotype, specifically the absence of the common 19-CA repeat allele in the promoter region of the IGF1 gene, in combination with oral contraceptive (OC) use or parity on breast volume and IGF-1 levels. MATERIALS AND METHODS: Two hundred fifty-eight healthy women, </=40 years old, from hereditary breast cancer families participated in this prospective study. Twenty-three women were known BRCA1 mutation carriers, 7 women were known BRCA2 mutation carriers, 54 women were noncarriers from BRCA1/2 families, 111 women belonged to breast cancer families where no BRCA1 or BRCA2 mutations were detected, and 63 women were untested from high-risk breast cancer families. All women completed a questionnaire including information on reproductive factors and OC use. We measured height, weight, breast volumes, and plasma IGF-1 levels once during menstrual cycle days 5-10 and once again during menstrual cycle days 18-23. The IGF1 genotype was successfully analyzed with polymerase chain reaction and fragment analyses in 254 women. RESULTS: Thirteen percent had no IGF1 19-CA repeat allele. The absence of the 19-CA repeat allele was more common among women with known BRCA1 mutations compared to other women (26% versus 12%; P= 0.05). See updated and revised Table 1 from original publication. IGF-1 levels were similar among parous and nulliparous women not using OCs, which is in contrast to results from women in the general population, where parous women have lower IGF-1 levels than nulliparous women. Furthermore, OC use did not affect IGF-1 levels in parous women in our study. BRCA mutation status did not affect age-adjusted IGF-1 levels in either cycle phase among nonusers. Most of the nulliparous OC users had lower IGF-1 levels than nonusers. However, there was an interaction between IGF1 genotype and OC use on IGF-1 levels in nulliparous women (P= 0.026). Compared with nonusers, IGF-1 levels were highly suppressed in OC users with a 19-CA repeat allele (P < 0.001), but not among women lacking the 19-CA repeat allele (P= 0.81). We also observed an interaction between parity and IGF1 genotype on breast volume (P= 0.01). Absence of the 19-CA repeat allele was associated with larger breast volumes in parous versus nulliparous women and OC users, while parous women and OC users with the 19-CA repeat allele had smaller breast volumes than nulliparous women and nonusers adjusted for body weight. During follow-up, six incident breast cancers cases occurred, four in known BRCA1 mutation carriers and two in untested women. Incident breast cancers were associated with absence of the 19-CA repeat allele (log-rank; P= 0.002). CONCLUSION: Our results suggest that absence of the IGF1 19-CA repeat allele modifies IGF-1 levels, breast volume, and possibly early-onset breast cancer risk after hormone exposure in young, high-risk women. These results warrant confirmation in a larger prospective cohort of high-risk women. If confirmed, the IGF1 genotype could be incorporated as an additional marker to improve risk estimates for early-onset breast cancer during genetic counseling of women from high-risk breast cancer families.

Age of Onset↗

PubMed1998

[Insulin-like growth factor 1 regulates collagen synthesis of periodontal ligament cells by a mechanism involving inhibition of poly(ADP-ribose) synthesis].

OBJECTIVE: To investigate the effect of IGF1 on collagen synthesis of PDL cells and the intracellular mechanism of IGF1 action on collagen synthesis. METHODS: Cultured human periodontal ligament cells were used, collagen synthesis, lactate production, PADPR synthesis and PADPR synthetase activity under the action of IGF1 at various concentration for 16 hours were analysed. RESULTS: (1) IGF1 stimulates collagen synthesis of cultured PDL cell. (2) IGF1 increases lactate production of PDL cells, which can be negated by 2-DG. (3) IGF1 decreases PADPR synthesis through inhibiting PADPR synthetase activity of PDL cells. (4) exogenous NAD+ attenuates stimulated collagen synthesis by IGF1 on PDL cells. CONCLUSION: IGF1 stimulates collagen synthesis of PDL cells through inhibiting PADPR synthesis by acting at increasing lactate production which lowers intracellular NAD+ level and at suppressing PADPR synthetase activity. It strongly suggests that PADPR is an intracellular mediator of IGF1 action on collagen synthesis.

Cells, Cultured↗

PubMed1994

Growth factor-regulated phosphatidylinositol-3-kinase in astrocytes. Involvement of pp60c-src.

Growth factors differently regulate astroglial cell differentiation and proliferation. In an effort to understand the early intracellular events promoted by growth factors in astroglial cells, we have determined the effects of IGF1, insulin, PDGF, EGF and FGFs on phosphatidylinositol-3 kinase. IGF1, PDGF and EGF which stimulate cell proliferation of astroglial cells, increased phosphatidylinositol-3 kinase activity immunoprecipitated with anti-phosphotyrosine antibodies as shown by thin layer chromatography and high performance liquid chromatography. FGFa and FGFb, which strongly stimulate proliferation of astroglial cells, have no effect on phosphatidylinositol-3 kinase activity. Addition of 1 nM PDGF, 10 nM IGF1 or 100 nM EGF to the culture medium rapidly stimulated phosphatidylinositol-3 kinase activity which declined slowly after 2 min. The stimulation of phosphatidylinositol-3 kinase increased with growth factor concentration. The maximum increase in phosphatidylinositol-3 kinase activity occurred with 50 nM IGF1, 1 nM PDGF or 100 nM EGF. Since insulin was active only at high concentration (1 microM), its effect was probably mediated through IGF1 receptors and not through insulin receptors. Treatment with IGF1-plus-EGF, had an additive effect on PI(3)-kinase activity, PDGF-plus-IGF1 did not. IGF1 and PDGF, to a lesser degree, also increased the phosphatidylinositol-3 kinase activity associated with pp60c-src protein. Immunoblots performed with an antibody directed against the p85-subunit of the phosphatidylinositol-3 kinase confirmed that IGF1 increased the number of phosphatidylinositol-3 kinase molecules associated with phosphotyrosine-containing proteins or with c-src protein. Each growth factor affects in a different manner the association of phosphatidylinositol-3 kinase with phosphotyrosine-containing proteins and with c-src protein and thus probably modulates intracellular signals downstream of phosphatidylinositol-3 kinase in astroglial cells.

Animals↗

PubMed1996

Regulation of human dermal papilla cell production of insulin-like growth factor binding protein-3 by retinoic acid, glucocorticoids, and insulin-like growth factor-1.

Insulin-like growth factor-1 (IGF1) has been reported to stimulate hair elongation and to facilitate maintenance of the hair follicle in anagen phase. However, little is known about IGF1 signaling in the hair follicle. In this study we investigate the effects of IGF1, glucocorticoids, and retinoids on dermal papilla (DP) cell production of insulin-like growth factor binding proteins (IGFBPs). IGFBPs comprise a family of IGF binding proteins that are produced and released by most cell types. They bind to IGFs to either enhance or inhibit IGF activity. In the present report we identify IGFBP-3 as being produced and released by cultured human dermal papilla (DP) cells. IGFBP-3 levels are increased fivefold by retinoic acid, eightfold by dexamethasone, and tenfold by IGF1. DP cells are known to produce IGF1, and so the observed stimulation of DP cell IGFBP-3 production by IGF1 is consistent with the idea that DP cells possess the IGF transmembrane receptor kinase and are autoregulated by IGFs. The level of another IGFBP, tentatively identified as IGFBP-2, is, in contrast, not regulated by these agents. IGFBP-3 has been shown to inhibit the activity of IGFs in a variety of systems. Our results are consistent with a model in which retinoids and glucocorticoids inhibit IGF action on DP cells and surrounding matrix cells by stimulating increased DP cell production of IGFBP-3. The IGFBP-3, in turn, forms a complex with free IGF1 to reduce the concentration of IGF1 available to stimulate hair elongation and maintenance of anagen phase.

Cells, Cultured↗

PubMed2004

Signaling by insulin-like growth factor 1 in brain.

The homologous insulin and insulin-like growth factor (IGF) receptors are both expressed in the brain, in overlapping but distinct neuroanatomical patterns. In contrast to insulin, IGF1 is also highly expressed within the brain and is essential for normal brain development. IGF1 promotes projection neuron growth, dendritic arborization and synaptogenesis. IGF1 acts in an autocrine and/or paracrine manner to promote glucose utilization, using phosphatidylinositol 3 kinase (PI3K)/Akt, also known as protein kinase B (PKB)/glycogen synthase kinase 3beta (GSK3beta) pathways similar to insulin signaling in peripheral tissues. IGF1 promotes neuronal survival during normal brain development mainly in hippocampal and olfactory systems that depend on postnatal neurogenesis. IGF1's anabolic and neuroprotective roles may be coordinated by inhibition of GSK3beta. The identification of GSK3beta as a major target of brain IGF1 signaling provides a unifying pathway for IGF1's well-established anabolic and anti-apoptotic functions, with IGF1-induced inhibition of GSK3beta triggering multifaceted anabolic and neuroprotective effects.

Animals↗

PubMed1999

Expression of insulin-like growth factor-1 receptor in human colorectal cancer.

The activation of the insulinlike growth factor 1/IGF-1 receptor system (IGF1/IGF1-R) has recently emerged as critical event in transformation and tumorigenicity of several murine and human tumors. Expression of IGF1 and of IGF1-R has been demonstrated in normal and neoplastic intestinal cell lines of rats and humans. However, the modulation of IGF1-R expression during the progression from normal colonic mucosa to adenoma, to carcinoma, and to metastasis, has not been evaluated. In this retrospective study, we investigated the expression of IGF1-R in 12 colonic adenomas (AD), 36 primary colorectal adenocarcinomas (CA), and in 27 corresponding metastases (MT). Normal colonic mucosa (N) was adjacent to the CA in 34 cases. Formalin-fixed, paraffin-embedded tissues of each case were immunostained using the avidin-biotin-peroxidase method. We used an anti-IGF1-R rabbit polyclonal antibody (Santa Cruz Biotechnology, CA; dilution 1:100). Positive staining was quantitated by CAS-200. Moderate to strong cytoplasmic immunostaining was observed in 34 of 36 CA (96%), and in 25 of 27 MT (93%). In all of the positive MTs, the intensity of the staining was always strong. In 10 of 12 ADs (83%), only a faint cytoplasmic stain was identified. Normal mucosa when present was negative. Strong IGF1-R positivity correlated with higher grade and higher-stage tumors (P < .01). These data suggest a role of IGF1-R expression during the progression of colorectal adenoma to carcinoma. An increased number of IGF1-R receptors may favor the metastasis of colorectal cancer.

Adenocarcinoma↗

PubMed2003

Initiation factor 2B activity is regulated by protein phosphatase 1, which is activated by the mitogen-activated protein kinase-dependent pathway in insulin-like growth factor 1-stimulated neuronal cells.

We have previously demonstrated that insulin-like growth factor 1 (IGF1) induces eukaryotic initiation factor 2B (eIF2B) activation in neuronal cells through the phosphatidylinositol 3 kinase/glycogen synthase kinase 3 pathway as well as by activation of the mitogen-activated protein kinase (MAPK)-activating kinase (MEK)/MAPK signaling pathway (Quevedo, C., Alcázar, A., and Salinas, M. (2000) J. Biol. Chem. 275, 19192-19197). This paper addresses the mechanism involved in IGF1-induced eIF2B activation via the MEK/MAPK cascade in cultured neurons treated with IGF1 and demonstrates that extracellular signal-regulated MAP kinase 1 and 2 (ERK1 and -2) immunoprecipitates of IGF1-treated neuronal cells promote this activation. This effect did not directly result from eIF2B phosphorylation by ERK immunoprecipitates. In addition, recombinant ERK1 and -2 neither activate eIF2B nor phosphorylate it. Endogenous protein phosphatase 1 and 2A catalytic subunits (PP1C and PP2AC, respectively) were co-immunoprecipitated with ERK1 and -2, and the association of ERK with PP1C was stimulated by IGF1 treatment, resulting in increased PP1 activity. ERK immunoprecipitates incubated with PP1 inhibitors did not activate eIF2B, indicating that PP1C activates eIF2B. In vitro experiments with phosphorylated eIF2B showed that recombinant PP1C (alpha isoform) dephosphorylates and activates eIF2B. Paralleling eIF2B activation, IGF1 treatment induced PP1 activation in a MEK/MAPK-dependent fashion. Moreover, the treatment of neurons with the PP1 inhibitor tautomycin inhibited PP1 activation and prevented IGF1-induced eIF2B activation. These findings strongly suggest that IGF1-induced eIF2B activation in neurons is effected by PP1, the activation of which is mediated by the MEK/MAPK signaling pathway.

Animals↗

PubMed1988

A comparison of follicular fluid levels of insulin-like growth factor-1 in normal dominant and cohort follicles, polycystic and multicystic ovaries.

Fourteen ovulatory patients undergoing diagnostic laparoscopy had at least two samples of clear follicular fluid (FF) collected in the late follicular phase. The cohort concentrations of Insulin-like Growth Factor-1 (IGF1) were significantly correlated with serum IGF1 and dominant follicles contained significantly higher concentrations of IGF1 and oestradiol (E2) than their cohorts. After the LH surge, a further significant increase in dominant FF-IGF1 occurred. FF-(log)E2 was significantly correlated with both FF-IGF1 and FF volume. Nine women with the polycystic ovary syndrome (PCOS) and one patient with multicystic ovaries (MCO) associated with weight-loss related amenorrhoea also had follicular aspiration performed. The mean (SD) FF-IGF1 in the PCOS group, 0.42 (0.15) U/ml, was not significantly different from that of the cohorts in the control group, 0.39 (0.13) U/ml. The patient with MCO had both serum and FF-IGF1 concentrations less than 10th centile. These results support the hypothesis that IGF1 has a paracrine (and possibly endocrine) role in the regulation of ovarian function in the human female.

Adult↗

PubMed1999

IGF-I deficient mice show reduced peripheral nerve conduction velocities and decreased axonal diameters and respond to exogenous IGF-I treatment.

Although insulin-like growth factor-I (IGF-I) can act as a neurotrophic factor for peripheral neurons in vitro and in vivo following injury, the role IGF-I plays during normal development and functioning of the peripheral nervous system is unclear. Here, we report that transgenic mice with reduced levels (two genotypes: heterozygous Igf1+/- or homozygous insertional mutant Igf1m/m) or totally lacking IGF-I (homozygous Igf1-/-) show a decrease in motor and sensory nerve conduction velocities in vivo. In addition, A-fiber responses in isolated peroneal nerves from Igf1+/- and Igf1-/- mice are impaired. The nerve function impairment is most profound in Igf1-/- mice. Histopathology of the peroneal nerves in Igf1-/- mice demonstrates a shift to smaller axonal diameters but maintains the same total number of myelinated fibers as Igf1+/+ mice. Comparisons of myelin thickness with axonal diameter indicate that there is no significant reduction in peripheral nerve myelination in IGF-I-deficient mice. In addition, in Igf1m/m mice with very low serum levels of IGF-I, replacement therapy with exogenous recombinant hIGF-I restores both motor and sensory nerve conduction velocities. These findings demonstrate not only that IGF-I serves an important role in the growth and development of the peripheral nervous system, but also that systemic IGF-I treatment can enhance nerve function in IGF-I-deficient adult mice.

Animals↗