Expression Of Insulin-like Growth factor-II Research Articles

Insulin-like growth factor II mRNA is expressed in neurones of the brain of the bony fish Oreochromis mossambicus, the tilapia.

The physiological meaning of insulin-like growth factor II (IGF-II) is still enigmatic. IGF-II occurs in the adult mammalian brain where it is expressed in the mesodermal portion of the choroid plexus and the meninges, but results on its presence in cells of neuroepithelial origin are controversial. However, IGF-II mRNA is transiently expressed in neurones during mammalian early development. In bony fish, IGF-II mRNA is also present in the adult brain but nothing is known about its synthesis sites. Thus, the present study using in situ hybridization with digoxigenin-labelled RNA species-specific probes investigates the cellular distribution of IGF-II mRNA in the adult brain of a bony fish, the tilapia (Oreochromis mossambicus). As in mammals, IGF-II mRNA was strongly expressed in the choroid plexus and meninges. Thus, IGF-II synthesis by choroid plexus and meninges seems to have a long evolutionary history and may be common to all vertebrates. However, as shown by the detailed investigation of landmark nuclei and regions, IGF-II mRNA occurred also in numerous neurones at all levels of the tilapia brain. The distinct localization of IGF-II mRNA in neurones might indicate that neuronal IGF-II acts as transmitter or modulator. However, the widespread occurrence of the IGF-II-producing neurones argues against this assumption and most probably suggests that IGF-II plays a role in the differentiation, maintenance and regeneration of neurones. It is further assumed that the sustained neuronal IGF-II expression in the brain of the adult tilapia correlates with continued post-embryonic up to life-long brain growth as has been shown in many teleost fishes.

PTEN modulates insulin-like growth factor II (IGF-II)-mediated signaling; the protein phosphatase activity of PTEN downregulates IGF-II expression in hepatoma cells

The PTEN gene (phosphatase and tensin homologous on chromosome 10) is frequently mutated or deleted in a number of malignancies including human hepatocellular carcinoma (HCC). We reported previously that the hepatitis B virus X (HBx) protein, known to be a causative agent in the formation of HCC, activates insulin-like growth factor II (IGF-II) expression through Sp1 phosphorylation by protein kinase C (PKC) or mitogen-activated protein kinase (MAPK) signaling. In this report we demonstrate that the PTEN effect on HBx induced IGF-II activation in a hepatoma cell line. Expression of PTEN and IGF-II was inversely related in different hepatoma cell lines. PTEN expression induced decreased Sp1 DNA binding by dephosphorylating Sp1 and interfered with transcriptional transactivation of IGF-II by HBx in hepatoma cells. The protein phosphatase activity was involved in PTEN downregulation of IGF-II transcription through downregulation of MAPK, MAPK kinase phosphorylation and PKC translocation. Our data suggest that PTEN blocks Sp1 phosphorylation in response to HBx, by inactivating PKC, MAPK and MAPK kinase which eventually downregulate IGF-II expression, during the formation of HCC.

Effect of maternal body condition on placental and fetal growth and the insulin-like growth factor axis in Dorset ewes

This study investigated the effects of maternal body condition on fetal growth. Fetal and placental parameters from Dorset ewes of body condition score 2.0 (lean, n = 5), 3.5 (moderate, n = 7) and 5.0 (fat, n = 4) at mating were studied on day 65 of gestation. The fetal weight and fetal weight:crown-rump length ratio were greater in fat ewes than in ewes of moderate condition. The raised total and mean placentome weight in fat ewes compared with ewes of moderate condition may have contributed to their increased fetal growth. However, the fetal crown-rump length was not affected. With in situ hybridization, insulin-like growth factor II (IGF-II) mRNA and insulin-like growth factor binding protein 2 (IGFBP-2), -3 and -6 were all detected in the placentome capsule; IGF-II mRNA was also found in the mesoderm of the fetal villi and IGFBP-3 and IGFBP-6 were present in the caruncular stroma of the maternal villi. Ewes of moderate condition, which had the smallest placentae, had the greatest placental expression of IGF-II, IGFBP-2 and IGFBP-3. In the intercotyledonary endometrium, IGFBP-3, IGFBP-5 and uterine milk protein (UTMP) mRNA were all expressed in the glandular epithelium. IGFBP-3 and IGFBP-5 absorbance values were lowest in the lean ewes, whereas UTMP values were highest. Maternal insulin concentrations were greater in fat ewes, whereas plasma glucose and IGF-I concentrations in the fetal compartment were lowest in fat ewes. Therefore, in obese ewes, fetal and placental growth is increased in mid-gestation in association with higher maternal insulin concentrations and lower expression of IGFBPs in the maternal placentomes. Placental and fetal development in lean ewes may be promoted by reduced IGFBP expression in the placentomes and enhanced UTMP production by the endometrial glands. The ewes of moderate condition had the smallest fetuses and placentae coupled with the highest placental expression of IGF-II and IGFBPs.

Expression of insulin-like growth factor-II and insulin-like growth factor binding protein-1 in the placental basal plate from pre-eclamptic pregnancies

Objectives: To determine whether expressions of insulin-like growth factor-II (IGF-II) and insulin-like growth factor binding protein-1 (IGFBP-1) are altered in pre-eclamptic placenta and to elucidate the possible relationship between their expressions and a mechanism for inadequate trophoblast invasion in pre-eclampsia. Methods: Placental tissues were obtained at cesarean delivery from five normotensive, nine mild pre-eclamptic and five severe pre-eclamptic women at 33–39 completed weeks of gestation. After total ribonucleic acid was extracted, reverse transcriptase-polymerase chain reaction was performed to determine IGF-II and IGFBP-1 mRNA expression. Product bands were quantitated by scanning densitometry and results were expressed as ratio of cytokines/β-actin. Western blot analysis was also done to determine IGF-II and IGFBP-1 protein expression. Statistical analysis was determined by Kruskal–Wallis analysis of variance with the Scheffe multiple post-hoc test. Results: The IGF-II mRNA levels of mild and severe pre-eclamptic placenta were significantly lower than that of uncomplicated placenta (P<0.005, P<0.001, respectively), with the level of severe pre-eclamptic placenta being significantly lower than that of mild pre-eclamptic placenta (P<0.05). As for the IGF-II protein expression, a significant decrease was found among the three groups (P<0.001), correlating with the IGF-II mRNA results. However, the mean IGFBP-1 mRNA levels of mild and severe pre-eclamptic placenta were significantly higher than that of uncomplicated placenta (P<0.05, P<0.005, respectively), with the level of severe pre-eclamptic placenta being significantly raised compared with that of mild pre-eclamptic placenta (P<0.05). Finally, a significant increase of IGFBP-1 protein expression was noted among the three groups (P<0.001), correlating with the IGFBP-1 mRNA results. Conclusions: This study suggests that IGF-II and IGFBP-1 might be associated with the impaired trophoblastic invasion that may lead to pathogenesis of pre-eclampsia.

Effect of refeeding on IGFI, IGFII, IGF receptors, FGF2, FGF6, and myostatin mRNA expression in rainbow trout myotomal muscle

Fish endure long periods of fasting and demonstrate an extensive capacity for rapid and complete recovery after refeeding. The underlying mechanisms through which nutrient intake activates an increase in somatic growth and especially in muscle growth is poorly understood. In this study we examined the expression profile of major muscle growth regulators in trout white muscle 4, 12, and 34 days after refeeding, using real-time quantitative RT-PCR. Mean insulin-like growth factor I (IGFI) mRNA level in muscle increased dramatically 8- and 15-fold, 4 and 12 days, respectively, after refeeding compared to fasted trout. This declined thereafter. Conversely, only a weak but gradual increase in mean insulin-like growth factor II (IGFII) mRNA level was observed during refeeding. Inversely to IGFI, mean IGF receptor Ia (IGFRIa) mRNA level declined after ingestion of food. In contrast, IGF receptor Ib (IGFRIb) mRNA level was not affected by refeeding. Mean fibroblast growth factor 2 (FGF2) mRNA level increased by 2.5-fold both 4 and 12 days after refeeding, whereas fibroblast growth factor 6 (FGF6) and myostatin mRNA levels were unchanged. Subsequent to IGFI and FGF2 gene activation, an increase in myogenin mRNA accumulation was observed at 12 days post-refeeding suggesting that an active differentiation of myogenic cells succeeds their proliferation. In conclusion, among the potential growth factors we examined in this study, IGFI and FGF2 were identified as candidate genes whose expression may contribute to muscle compensatory growth induced by refeeding.

Loss of imprinting of IGF-II gene in children with acute lymphoblastic leukemia

Insulin-like growth factor-II (IGF-II) is known to be involved in the regulation of growth, differentiation and cell death in normal human tissues. In a variety of human tumors, the IGF-II gene is overexpressed and considered to be a stimulator for tumor growth through autocrine and paracrine mechanisms. The IGF-II gene is normally parental imprinted, only the paternal allele being expressed in most tissues. Several reports about biallelic expression (loss of imprinting (LOI)) of the IGF-II gene in different tumors suggest a role of dysregulation of IGF-II imprinting in tumorigenesis. However, biallelic expression of IGF-II gene has also been reported in different tissues of a significant number of normal controls, indicating either a normal phenomenon or an elevated cancer risk in this group of persons. Although LOI of IGF-II presumably promotes tumorigenesis by increasing IGF-II expression, elevated IGF-II levels in those patients have not been reported. We studied IGF-II gene expression in malignant lymphoblasts of 124 children suffering from acute lymphoblastic leukemia, 196 cord blood samples from healthy newborns and mononuclear cells (MNC) from 50 healthy age matched children. The ApaI polymorphism in exon 9 of the IGF-II gene and allele-specific exon-connection RT-PCR was used for determination of the imprinting status. From 44 informative ALL-patients, 24 (54%) showed LOI of the IGF-II gene. Twenty percent of the informative cord blood samples ( N=56) and 14% of the informative MNC samples from healthy controls ( N=22) showed biallelic expression of IGF-II. In the ALL-patients, no statistical significant correlation between LOI patients and relapse rate, surviving rate and risk groups could be detected. We conclude that LOI of IGF-II occurs in malignant lymphoblasts of children suffering from acute lymphoblastic leukemia in more than 50% of the patients. In MNC from cord blood and peripheral MNC from healthy controls, biallelic expression could be detected in up to 20% of all cases. The importance of LOI in ALL-patients needs to be further evaluated to determine its impact in leukemogenesis.

Relaxin causes proliferation of human amniotic epithelium by stimulation of insulin-like growth factor-II

Objective: The study was conducted to determine whether relaxin has a proliferative effect on amniotic epithelial cells and to show that this effect is caused by its stimulation of the insulin-like growth factor-II (IGF-II) gene. Study Design: Immunolocalization and Northern analysis were used to confirm the expression of IGF-II by the fetal cells in the membranes. Human amniotic epithelial (WISH) cells were treated with doses of IGF-II or human relaxin and their proliferative effects measured. The mechanism of the effect of relaxin on cellular proliferation was studied with the use of an IGF-II-blocking antibody and Northern analysis for IGF-II gene expression after treatment with relaxin. An in vivo correlate was sought by quantitation of relaxin gene expression in 10 fetal membranes from women with normally grown and large for gestational age infants. Results: The amniotic epithelial and cytotrophoblast cells of the fetal membranes expressed IGF-II, as did the amniotic epithelial-like (WISH) cell line. Treatment of WISH cells with IGF-II or relaxin caused a significant (P < .03) and dose-related increase in WISH cell proliferation over 5 days. The concurrent treatment with a blocking antibody to IGF-II significantly decreased the proliferative response to IGF-II (P < .002) and relaxin (P < .002). Treatment with relaxin caused a significant increase (P < .003) in the transcription of IGF-II in 24 hours. In fetal membranes, the levels of relaxin gene expression correlated with fetal membrane surface area (r = 0.76) and was significantly greater (P < .008) in the membranes from macrosomic infants (4020-4729 g) compared with those normally grown (2855-3830 g). Conclusion: IGF-II and relaxin both caused the proliferation of WISH cells. Concurrent treatment with an IGF-II-blocking antibody abrogated the proliferative effects of both hormones. Relaxin increased the transcription of IGF-II, and its expression levels in the fetal membranes correlated with the membrane surface area as well as neonatal birth weight. These data suggest that relaxin is a growth factor for the fetal membranes. Am J Obstet Gynecol 2003;188:234-41.

The Regional Expression of Insulin-like Growth Factor II (IGF-II) and Insulin-like Growth Factor Binding Protein-1 (IGFBP-1) in the Placentae of Women with Pre-eclampsia

Insulin-like growth factors and their binding proteins regulate cellular proliferation, differentiation and function, and play an important role in placental development. IGF-II and IGFBP-1 are abundantly expressed by cells at the maternal-fetal interface and mediate cell-to-cell communication between trophoblasts and decidua. Placentae of pre-eclamptic pregnancies show villous cytotrophoblast proliferation, increased syncytial sprout formation and impaired trophoblast invasion. We hypothesized that the expression of IGF-II and IGFBP-1 by cells at the maternal-fetal interface is altered in pre-eclampsia. We determined the regional abundance and cellular localization of IGF-II mRNA and IGFBP-1 mRNA and protein in placentae from normotensive control and pre-eclamptic pregnancies. IGF-II mRNA was expressed in both the chorionic villi and basal plate decidua regions. Increased IGF-II mRNA abundance was observed in the intermediate trophoblasts of peri-infarct regions. IGFBP-1 expression was present only in the decidua of the basal plate and membranes, and this expression was decreased significantly in pre-eclamptic placentae. The increased IGF-II expression in the intermediate trophoblast surrounding placental infarcts suggests a role for IGF-II in placental repair or remodelling. Decreased IGFBP-1 mRNA expression in the basal plate decidua suggests that the increased concentrations of IGFBP-1 the circulation of pre-eclamptic women is not of decidual origin. The altered IGF-II and IGFBP-1 expression at the fetomaternal interface may be important in the pathophysiology of pre-eclampsia.

Alterations in promoter usage and expression levels of insulin-like growth factor-II and H19 genes in cervical carcinoma exhibiting biallelic expression of IGF-II

Biallelic expression of insulin-like growth factor-II (IGF2) has been reported to be associated with progression of several tumors. Here, we report that the promoter usage and expression levels of IGF2 and H19 were altered in cervical carcinoma showing loss of imprinting. The imprinting status was examined in 32 cervical carcinomas and their matched normal tissues. Loss of imprinting (LOI) of IGF2 was observed in seven of 18 (39%) informative cases. LOI of H19 gene was detected in five of 14 informative cases. The usage of promoter P1 was observed in LOI tumors of IGF2, but not in the tumors showing maintenance of IGF2 imprinting (MOI) and in the normal cervical tissues. Unlike MOI tumors, some LOI tumors revealed the lack of IGF2 transcription from promoter P3. LOI tumors of IGF2 showed an increased expression level of IGF2 but a down-regulation of H19 relative to the normal tissues whereas MOI tumors did not reveal significant alterations. These results suggest that promoter P1 could be involved in the biallelic expression of IGF2 and that the altered expression levels of IGF2 and H19 gene might be associated with the progression of cervical carcinoma showing biallelic expression of IGF2.

Kinetics and regulation of site-specific endonucleolytic cleavage of human IGF-II mRNAs.

Human insulin-like growth factor II (IGF-II) mRNA can be cleaved at a specific site in its 4 kb long 3'-UTR. This yields a stable 3' cleavage product of 1.8 kb consisting of a 3'-UTR and a poly(A) tail and an unstable 5' cleavage product containing the IGF-II coding region. After cleavage, the 5' cleavage product is targeted to rapid degradation and consequently is no longer involved in IGF-II protein synthesis. Cleavage is therefore thought to provide an additional way to control IGF-II gene expression. In this paper the kinetics and the efficiency of cleavage of IGF-II mRNAs are examined. The cleavage efficiency of IGF-II mRNAs carrying four different leaders (L1-L4) is enhanced in the highly structured leaders L1 and L3. Additionally, under standard cell culture conditions cleavage is a slow process that only plays a limited role in destabilisation and translation of the IGF-II mRNAs. However, in human Hep3B cells and CaCo2 cells which express IGF-II endogenously, cleavage is upregulated 3-5-fold at high cell densities. Regulated endonucleolytic cleavage of IGF-II mRNAs is restricted to cells in which IGF-II expression is related to specific cell processes.

Study on the Expression of Insulin-like Growth Factor II (IGF- II) in Hepatocellular Carcinoma Cells and Developing Rat Embryos.

The insulin-like growth factor II (IGF-II) gene expresses a family of transcripts in embryonic/fetal tissue, and also highly was expressed during hepatocellular carcinogenesis. In this study, we showed that IGF-II mRNA and protein levels are detected in rat embryo, HepG2 human hepatoma cells and Chang liver cells. This study included sections of rat embryos 7~17 days post coitum (d.p.c), HepG2 cells and Chang liver cells. Using immunohistochemistry, Northern blotting and Western blotting, we observed the expression of IGF-II in the rat embryo, HepG2 cells and Chang liver cells. We localized IGF-II gene products in sections of rat embryo 7~17 d.p.c by performing immunohistochemistry. The IGF-II was mainly expressed in the proximal endoderm and ectoplacental cone between 7 and 9 d.p.c. At 10 d.p.c. the expression was localized at the heart primodium as well as the proximal endoderm, and at 11 d.p.c. the IGF-II was expressed in the liver and heart. After 12 d.p.c. and 14 d.p.c., the expression was also detected in the brain, muscle and bone, and head mesenchyme, respectively. While the expression of IGF-II protein was not detected in the normal adult liver, intense staining was detected in the heart, liver and choroids plexus at 17 d.p.c. These results suggest that IGF-II may act as an oncofetal protein during hepatocellular carcinogenesis and embryogenesis.

Hepatitis C virus core protein transactivates insulin-like growth factor II gene transcription through acting concurrently on Egr1 and Sp1 sites.

The possibility that hepatitis C virus core gene product (HCV-core) acts as a transactivator in insulin-like growth factor II (IGF-II) gene transcription was tested. HCV-core protein increases endogenous IGF-II expression from promoter 4 (P4) of the IGF-II gene through two cis-acting elements: Sp1 and Egr1 binding sites. Sp1 and Egr1 both bind to IGF-II P4 and functionally cooperate in mediating the maximal activity of IGF-II P4. HCV-core protein induced the binding of Sp1 and Egr1 on its binding sites on IGF-II P4. In addition, Sp1 and Egr1 were stimulated to phosphorylate by HCV-core, and its DNA binding activity was up-regulated upon HCV-core transfection. Transfection with HCV-core in HepG2 cells stimulated the membrane translocation of protein kinase C (PKC) and the treatment of HCV-core transfected cells with calphostin C, a PKC inhibitor, blocked induction of Sp1 and Egr1 DNA binding activity, and eventually transcriptional transactivations of the IGF-II gene. Increasing the DNA binding activity of the phosphorylated form of Sp1 and Egr1 might be an important mechanism for regulating IGF-II gene expression and for promoting cell division during hepatic carcinogenesis. These results indicate that HCV-core functions as a positive regulator of IGF-II transcription through the PKC pathway and that Sp1 and Egr1 are direct targets of the transcriptional regulation of the IGF-II gene which plays an important role in hepatitis C virus pathogenesis during the formation of hepatocellular carcinoma (HCC).

Molecular significance of excess body weight in postmenopausal breast cancer patients, in relation to expression of insulin-like growth factor I receptor and insulin-like growth factor II genes.

A number of epidemiological and clinical studies have revealed that excess body weight increases the risk of postmenopausal breast cancer and also adversely affects subsequent malignant progression. To elucidate the molecular mechanisms underlying these observations, we examined mRNA expression of various genes in normal (non‐cancerous) mammary gland and cancer tissue of Japanese patients with primary breast cancer, in association with their body mass index (BMI). On the basis of analysis of 106 breast cancer patients, we found that mRNA expression of insulin‐like growth factor I receptor (IGF‐IR) and insulin‐like growth factor II (IGF‐II) in the normal mammary gland showed a significant and positive association with increased BMI among postmenopausal patients. Furthermore, the positive association of increased BMI with IGF‐IR mRNA expression was also found in postmenopausal breast cancer tissue, while this association was not observed among premenopausal patients. In addition, increased mRNA expression of cyclin Dl and bcl‐2 was observed in association with increased mRNA levels of IGF‐IR among the patients regardless of menopausal status. These findings suggest that the molecular consequence of the increased BMI is the increased expression of IGF‐II and IGF‐IR, resulting in development of postmenopausal breast cancer and its progression mediated through modulation of the cell cycle and apoptosis.

ONTOGENY OF THE H19 GENE IN SHEEP AND EFFECT OF MATERNAL FASTING ON ITS EXPRESSION IN THE FETUS

Mapped on the same chromosome as the Insulin-like Growth Factor II (IGF-II), an important factor regulating fetal growth, the H19 gene, is believed to play a role during embryogenesis and to share similar regulatory elements with IGF-II possibly by an enhancer competition system. This study was designed to characterize the ontogeny of H19 in sheep and the effect of maternal fasting on the expression of fetal IGF-II and H19 mRNA. A partial cDNA clone for the ovine H19 gene was isolated and used as a probe for RNase protection analysis. The ontogeny of H19 in liver, skeletal muscle and heart of ovine fetuses at 62, 100 and 130 days, lambs at 1 month and adult sheep revealed high tissue levels of H19 mRNA during fetal life that decreased significantly after birth. Maternal fasting significantly decreased fetal liver H19 mRNA expression but did not alter fetal IGF-II mRNA expression. These results suggest that H19, like IGF-II, may play an important role in the regulation of fetal growth and define an environmental condition whereby these two genes are regulated independently.

Induction of cellular genes is mediated by the Bel1 transactivator in foamy virus-infected human cells.

To gain insight into human foamy virus (HFV; also called spumaretrovirus)-induced alterations of cellular genes, the expression profiles of defined genes in HFV-infected primary human cells were analyzed by cDNA array assays. Several distinct cellular genes activated by HFV infection were identified; the identities of the cellular genes were confirmed by RNA blot analyses. Compared with mock-infected controls, the concentrations of cellular Kip2, Egr-1, COUP-TF1, insulin-like growth factor II (IGF-II), and EphB3 mRNAs were significantly increased in HFV-infected cells and showed a gene-specific and time-dependent induction. Immunoblot analyses with antibodies against some of the cellular gene products revealed increased levels of the corresponding proteins. To investigate mechanisms of HFV-induced alterations in cellular gene expression, the capacity of known HFV genes to increase expression of defined cellular genes was analyzed by transient expression experiments. Plasmids that encode the HFV Bel1 transcriptional transactivator were necessary and sufficient to strongly increase expression of p57Kip2, IGF-II, and EphB3 genes in 293T cells. Potential mechanisms and consequences of activation of cellular genes during HFV infection and Bel1 transactivation of the Kip2 gene are discussed.

Insulin-like growth factor II (IGF-II). Its role among regulatory peptides of the insulin superfamily

The review presents data on the insulin-like growth factor-II (IGF-II), a regulatory peptide included in the insulin superfamily, as its structure and function are the closest to those of insulin and IGF-I. The last decade investigations revealed the biological properties of IGF-II which distinguish it from related peptides. The primary sequence of the IGF-II structure has peculiar differences from those of insulin but insignificant ones from IGF-I. The tertiary structure of IGF-II is similar to that of the related peptide molecules, but a peculiar receptor-binding domain in the IGF-II molecule provides for its unique capability of interacting with receptors. IGF-II interacts with three types of receptors: receptors of IGF-I, IGF-2, and insulin. IGF-II has the highest affinity to IGF-2 receptors but its mitogenic effects are mediated by IGF-I receptors (i.e., the phenomenon of divergence of binding and biological activities). The arguments obtainedin vitro andin vivo are presented, which confirm propagation of mitogenic effects by IGF-I receptors but deny participation of IGF-2 receptors. The structural and functional bivalency of the M6P/IGF-2 receptor (a peculiar form of the M6P receptor in mammals) is considered in detail. The results of interactions of IGF-II and the M6P/IGF-2 receptors are not yet known. The primary function of the M6P/IGF-2 receptor (sorting and transport of the lysosomal enzymes) is likely to be due to the peptides inactivation and does not imply its participation in the IGF-II signaling. However, several data do not permit ruling out participation of the IGF-2 receptor in the IGF-II effects different from mitogenic ones. The organization of related peptide gene in the lancelet allows us to suggest the appearance of the IGF-II gene at the initial steps of the vertebrate evolution and to trace all stages of formation of two separate IGF genes up to the mammalian IGF-II and IGF-I genes with different structural organizations. The IGF-II expression by embryonic tissues is revealed earlier than that of other related peptides and reaches the highest level at the embryonal period. The general regularities of the IGF-II regulatory activity in embryogenesis and of the growth hormone effect on the IGF-II expression in embryonal tissues are considered.

Role of the IGF system in trophoblast invasion and pre-eclampsia.

Insulin-like growth factor-II (IGF-II) and IGF binding protein-1 (IGFBP-1) appear to play an important role in paracrine interactions at the maternal-fetal interface in human pregnancy. Patterns of expression of IGF-II and IGFBP-1 at the decidual-trophoblast interface suggest paracrine interactions occur between the IGF-II-expressing invading cytotrophoblast and maternal decidua-derived IGFBP-1. Autocrine/paracrine actions of trophoblast-derived IGF-II may be important in invasion, and for both trophoblast and decidual function. The actions of IGFBP-1 in binding IGF, and as an integrin ligand, suggest it may have multiple roles in the interactions between the invading trophoblast and the maternal decidua. Abundant decidual IGFBP-1 may interact with the IGF-II-expressing, protease-secreting trophoblast to modulate invasion. In-vitro studies of trophoblast-decidual cell interactions in invasion, and clinical observations in a gestational disorder with shallow placental invasion such as pre-eclampsia, have provided new insights into the possible role(s) of IGFBP-1 in trophoblast invasion. The precise mechanisms underlying IGF and IGFBP-1 action at the decidual-trophoblast interface remain to be elucidated. The potential predictive value of serum IGFBP-1 concentrations in pre-eclampsia also remains to be established.

Up-Regulation of Insulin-Like Growth Factor-II Expression Is a Feature of TrkA but Not TrkB Activation in SH-SY5Y Neuroblastoma Cells

The types of neurotrophin receptors that are expressed in neuroblastomas have different prognostic implications; trkA is a marker of good prognosis, whereas trkB expression is associated with poor prognosis. This suggests that either the signaling that is mediated via these receptors modulates the biological features of neuroblastoma cells differently, or that distinct lineages of sympathoadrenal precursors have been transformed. In this report, we evaluate the biological effects after activation of trkA or trkB by their major ligands in SH-SY5Y human neuroblastoma cells. Both trkA and trkB induce differentiation, inhibit growth, and promote the survival of cells under conditions of nutrient deprivation. However, the up-regulation of insulin-like growth factor-II (IGF-II) expression is a predominant feature of trkA activation by nerve growth factor (NGF). The growth inhibition induced by blocking the insulin-like growth factor-I receptor suggests that IGF-II is a component of the effector mechanism of trkA activation by NGF in trkA-transfected cells. Although trkA and trkB expression is associated with different prognoses in neuroblastoma, our study indicates that the effects mediated by these receptors in vivo may be quite similar for certain subsets of neuroblastomas.

A Low Protein Diet Alters the Balance of Islet Cell Replication and Apoptosis in the Fetal and Neonatal Rat and Is Associated with a Reduced Pancreatic Expression of Insulin-Like Growth Factor-II

A Low Protein Diet Alters the Balance of Islet Cell Replication and Apoptosis in the Fetal and Neonatal Rat and Is Associated with a Reduced Pancreatic Expression of Insulin-Like Growth Factor-II

A low protein diet alters the balance of islet cell replication and apoptosis in the fetal and neonatal rat and is associated with a reduced pancreatic expression of insulin-like growth factor-II.

A programmed turnover of pancreatic beta cells occurs in the neonatal rat involving a loss of beta cells by apoptosis, and their replacement by islet cell replication and neogenesis. The timing of apoptosis is associated with a loss of expression of a survival factor, insulin-like growth factor-II (IGF-II), in the pancreatic islets. Offspring from rats chronically fed a low protein isocalorific diet (LP) exhibit a reduced pancreatic beta cell mass at birth and a reduced insulin secretion in later life. This study therefore investigated the impact of LP on islet cell ontogeny in the late fetal and neonatal rat, and any associated changes in the presence of IGFs and their binding proteins (IGFBPs). Pregnant Wistar rats were fed either LP (8% protein) or normal (C) (20% protein) chow from shortly after conception until the offspring were 21 days postnatal (PN). Bromo-deoxyuridine (BrdU) was administered 1 h before rats were killed and pancreata removed from animals between 19.5 days fetal life and postnatal day 21. Offspring of rats given LP diet had reduced birthweight, pancreatic beta cell mass, and pancreas insulin content, with smaller islets compared with control fed animals, which persisted to weaning. Histological analysis showed that islets from pups given LP diet had a lower nuclear labeling index with BrdU in the beta cells, although, paradoxically, more beta cells showed immunoreactivity for proliferating cell nuclear antigen (PCNA). Because PCNA is present in G1 as well as S phase of the cell cycle, we quantified the number of beta cells immunopositive for cyclin D1, a marker of G1, and NEK2, an indicator of cells in G2 and mitosis. More beta cells in islets from LP-fed animals contained cyclin D1, but less contained NEK2 than did those in controls. This suggests that the beta cell cycle may have a prolonged G1 phase in LP-fed animals in vivo. Offspring of rats given C diet had a low rate of islet cell apoptosis detected by the TUNEL method in fetal and neonatal life (1-2%), with a transient increase to 8% at PN day 14. Offspring of rats receiving LP diet demonstrated a significantly greater level of islet cell apoptosis at every age, rising to 15% at PN 14. IGF-II mRNA was quantified in whole pancreas and was significantly reduced in LP-fed animals at ages up to PN day 10. IGF-II immunoreactivity within the islets of LP-fed rats was also less apparent, but no changes were seen in immunoreactive IGF-I or IGFBPs-2 to -5. These findings show that LP diet changes the balance of beta cell replication and apoptosis in fetal and neonatal neonatal life, which may involve an altered length of beta cell cycle, and contribute to the smaller islet size and impaired insulin release seen in later life. A reduced pancreatic expression of IGF-II may contribute to the lower beta cell proliferation rate and increased apoptosis seen in the fetus and neonate after feeding LP diet.