Insulin-like Growth Factor Signaling System Research Articles

Insulin-like growth factor signalling and its significance as a biomarker in fish and shellfish research.

The insulin-like growth factor signalling system comprises insulin-like growth factors, insulin-like growth factor receptors and insulin-like growth factor-binding proteins. Along with the growth hormones, insulin-like growth factor signalling is very pivotal in the growth and development of all vertebrates. In fishes, insulin-like growth factors play an important role in osmoregulation, besides the neuroendocrine regulation of growth. Insulin-like growth factor concentration in plasma can assess the growth in fishes and shellfishes and therefore widely applied in nutritional research as an indicator to evaluate the performance of selected nutrients. The present review summarizes the role of insulin-like growth factor signalling in fishes and shellfishes, its significance in aquaculture and in evaluating growth, reproduction and development, and discusses the utility of this system as biomarkers for early indication of growth in aquaculture.

Divergence and polymorphism analysis of IGF1Ra and IGF1Rb from orange-spotted grouper, Epinephelus coioides (Hamilton).

Orange-spotted grouper (Epinephelus coioides) is one of the most important marine fish and has a high market value. The insulin-like growth factor type 1 receptor (IGF1R) is a component of the insulin-like growth factor signaling system, and demonstrates important roles during growth. Based on information from livestock, we used IGF1R as a candidate gene to survey single nucleotide polymorphisms. In the present study, the sequences of IGF1Ra and IGF1Rb from orange-spotted grouper were obtained from the genome sequences and their clustering in clades a and b, respectively, was confirmed by phylogenetic analysis. Fourteen critical amino acids underlying functional divergence were detected between the two clades, revealing the molecular basis of their functional differences. Nearly one-fourth (22 kbp) of the genomic sequence of IGF1Ra was sequenced in a mass cross population, and nucleotide diversity and linkage disequilibrium levels were investigated. Nucleotide diversity was 0.00328 for π and 0.00344 for θw. The half decay of the squared allele-frequency correlation was 10,835 base pairs. Comparatively, the relatively high level of linkage and the significant deviation from neutrality-based codons in IGR1R showed that this gene was under selection. A site (KR269824.1:g. 63762C>T), located in the sixth intron, was significantly associated with eyeball diameter (P = 1.39 x 10-4, Q-value: 2.33 x 10-2), which accounted for 11.1% of phenotypic variance. These results highlight the important function of IGF1R in orange-spotted grouper and may be beneficial in the breeding of this species.

A progestin (17α,20β-dihydroxy-4-pregnen-3-one) stimulates early stages of spermatogenesis in zebrafish

Recently, evidence has been provided for multiple regulatory functions of progestins during the late mitotic and meiotic phases of spermatogenesis in teleost fish. For example, our previous studies suggested that 17α,20β-dihydroxy-4-pregnen-3-one (DHP), potentially via Sertoli cells that express the progesterone receptor (pgr) gene, can contribute to the regulation of zebrafish spermatogenesis. To further our understanding of the function of DHP at early spermatogenetic stages, we investigated in the present study the expression of genes reflecting Sertoli cell function and spermatogenic development in adult zebrafish testis after DHP treatment in tissue culture. Moreover, using an in vivo model of estrogen-mediated down-regulation of androgen production to interrupt adult spermatogenesis, we studied the effects of DHP on estrogen-interrupted spermatogenesis. In this model, DHP treatment doubled the testis weight, and all differentiating germ cell types, such as type B spermatogonia and primary spermatocytes, were abundantly present and incorporated the DNA-synthesis marker (BrdU). Accordingly, transcript levels of germ cell marker genes were up-regulated. Moreover, transcripts of two Sertoli cell-derived genes anti-müllerian hormone (amh) and gonadal soma-derived growth factor (gsdf) were up-regulated, as were three genes of the insulin-like growth factor signaling system, insulin-like growth factor 2b (igf2b), insulin-like growth factor 3 (igf3) and insulin-like growth factor 1b receptor (igf1rb). We further analyzed the relationship between these genes and DHP treatment using a primary zebrafish testis tissue culture system. In the presence of DHP, only igf1rb mRNA levels showed a significant increase among the somatic genes tested, and germ cell marker transcripts were again up-regulated. Taken together, our results show that DHP treatment induced the proliferation of early spermatogonia, their differentiation into late spermatogonia and spermatocytes as well as expression of marker genes for these germ cell stages. DHP-mediated stimulation of spermatogenesis and hence growth of spermatogenic cysts and the associated increase in Sertoli cell number may in part explain the elevated expression of Sertoli cell genes, but our data also suggest an up-regulation of the activity of the Igf signaling system.

Transcript abundance and apoptosis in day-7 porcine blastocyst cultured with exogenous insulin-like growth factor-I

Exogenous growth factors may increase the efficiency of embryo development in vitro. The aim of the present study was to examine the effects of insulin-like growth factor (IGF)-I on porcine embryo development. Porcine embryos obtained by in vitro fertilization were cultured for seven days in the presence of IGF-I (50, 100 or 150ng/ml). Subsequently, relative transcript abundance (RA) of IGF-related genes (IGFR1, IGFBP2, and IGFBP3), glucose transporter genes (SLC2A4 and SLC2A8), and apoptosis-related genes (BAX and BCL-XL) was analyzed. No differences were observed in the cleavage rate on day 2 post insemination (pi) and blastocysts rate on day 7pi between IGF-treated and control embryos. IGF-I treatment did not affect RA of IGFR1, IGFBP3, and SLC2A4 genes, but decreased RA of IGFBP2 and SLC2A8 genes. The percentage of TUNEL-positive nuclei in blastocysts did not differ between the experimental groups. However, RA of BAX and BCL-XL genes decreased in response to all IGF-I concentrations, whereas the BCL-XL/BAX RA ratio was enhanced when embryos were cultured in medium containing 150ng/ml of IGF-I. These results indicate that IGF-I did not stimulate in vitro development of porcine embryos through the IGF signaling system, nor did IGF-I stimulate RA of glucose transporter genes. However, IGF-I at the highest dose was able to increase the BCL-XL/BAX transcript expression ratio. This may indicate that the primary role of IGF-I during the first days of embryo development in the pig is associated with anti-apoptotic actions rather than with growth stimulation.

Targeting the insulin-like growth factor-1 receptor in human cancer

The insulin-like growth factor (IGF) signaling system plays a crucial role in human cancer and the IGF-1 receptor (IGF-1R) is an attractive drug target against which a variety of novel anti-tumor agents are being developed. Deregulation of the IGF signaling pathway frequently occurs in human cancer and involves the establishment of autocrine loops comprising IGF-1 or IGF-2 and/or IGF-1R over-expression. Epidemiologic studies have documented a link between elevated IGF levels and the development of solid tumors, such as breast, colon, and prostate cancer. Anti-cancer strategies targeting the IGF signaling system involve two main approaches, namely neutralizing antibodies and small molecule inhibitors of the IGF-1R kinase activity. There are numerous reports describing anti-tumor activity of these agents in pre-clinical models of major human cancers. In addition, multiple clinical trials have started to evaluate the safety and efficacy of selected IGF-1R inhibitors, in combination with standard chemotherapeutic regimens or other targeted agents in cancer patients. In this mini review, I will discuss the role of the IGF signaling system in human cancer and the main strategies which have been so far evaluated to target the IGF-1R.

Silencing of threeAmblyomma americanum(L.) insulin-like growth factor binding protein-related proteins prevents ticks from feeding to repletion

The insulin-like growth factor (IGF) binding proteins (IGFBP) family is the regulatory arm of the IGF signaling system that control mitogenic and anabolic actions of IGF peptide hormones. This study describes cloning and biological characterization of three Amblyomma americanum (L.) (Aam) proteins that show amino-terminal sequence and secondary structure similarity to the IGFBP superfamily. The three molecules here provisionally identified as AamIGFBP-rP1 and short (S) and long (L) AamIGFBP-rP6 are expressed in multiple tick organs and are responsive to tick feeding activity with the former being upregulated and the latter being downregulated. We show that they regulate tick physiological functions that may be related to A. americanum tick feeding success as revealed by RNAi-mediated dual silencing of AamIGFBP-rP6S and AamIGFBP-rP6L or AamIGFBP-rP1 alone, which caused a reduction in blood meal size compared to the controls. Additionally, in the case of AamIGFBP-rP1 silencing, 47% of ticks died while attempting to feed and those that did survive and spontaneously detached from the host failed to lay eggs. Although AamIGFBP-rP6S and AamIGFBP-rP6L show overall identities of 49% and 59%, respectively, to Rhipicephalus microplus C protein, the identity level jumps to ~84% when the comparison is restricted to first 70 amino acids of the mature protein. Similarly, the AamIGFBP-rP1 mature protein is ~72%, 87%, 88% and 92% identical to that of Ixodes scapularis S, R. microplus, R. appendiculatus N and A. variegatum F, respectively. The observed across-tick-species conservation suggests that the three molecules (AamIGFBP-rP1, AamIGFBP-rP6S and AamIGFBP-rP6L) represent target for development of vaccines to protect animals against multiple tick species. The data are discussed with reference to advances in tick molecular biology and the potential of the three proteins as targets for immunizing animals against tick feeding.

IGF-I, IGFBP-3, and IGF-I/IGFBP-3 Ratio: No Association with Incident Colorectal Cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study

The insulin-like growth factor (IGF) signaling system is thought to affect tissue growth and development ([1][1]), with IGF-I and IGF binding protein-3 (IGFBP-3) having putative procarcinogenic and anticarcinogenic properties, respectively. A recent meta-analysis of four prospective studies found

The type I insulin-like growth factor receptor pathway: a key player in cancer therapeutic resistance

The insulin-like growth factor (IGF) ligands stimulate cellular proliferation and survival by activating the type I insulin-like growth factor receptor (IGF-IR). As a result, the IGF signaling system is implicated in a number of cancers, including those of the breast, prostate, and lung. In addition to mitogenic and anti-apoptotic roles that may directly influence tumor development, IGF-IR also appears to be a critical determinant of response to numerous cancer therapies. This review describes the role of the IGF-IR pathway in mediating resistance to both general cytotoxic therapies, such as radiation and chemotherapy, and targeted therapies, such as tamoxifen and trastuzumab. It concludes with a description of approaches to target IGF-IR and argues that inhibition of IGF signaling, in conjunction with standard therapies, may enhance the response of cancer cells to multiple modalities.

IGF-IR: Potential Role in Antitumor Agents

As insulin-like growth factor (IGF) signaling has been recognized to play an important role in human cancer, the IGF-I receptor (IGF-IR) is currently the focus of intensive research aimed at developing novel antitumor agents. The IGF system is frequently deregulated in cancer cells by the establishment of autocrine loops involving IGF-I or -II and/or IGF-IR over-expression. Moreover, epidemiological studies have suggested a link between elevated IGF levels and the development of major human malignancies, such as breast, colon, lung and prostate cancer. Experimental therapies aimed at inhibiting IGF signaling in human tumors involve various approaches, including neutralizing antibodies and pharmacological inhibitors of IGF-IR kinase activity. Although there are numerous reports describing the antitumor activity of such agents against human cancer cell lines propagated in vitro or in experimental animals, it remains unclear how soon the existing drugs will have a demonstrable effect in patients. In this review, we will discuss the evidence implicating the IGF signaling system in the pathology of human cancer and the various strategies that have so far been developed to target the IGF-IR.

The Sirt1 deacetylase modulates the insulin-like growth factor signaling pathway in mammals

The lifespan of the nematode, Caenorhabditis elegans, can be extended by mutations affecting components of the insulin-like growth factor (IGF) signaling cascade or by overexpression of SIR2, an NAD +-dependent protein deacetylase. The mammalian homologue of SIR2, Sirt1, has been shown to modulate the activity of FoxO, a transcription factor that is downstream of the IGF signaling system. These results suggest that Sirt1 ought to affect the IGF pathway. We report here evidence that this is the case in mice. The loss of Sirt1 protein in mice results in increased expression of the IGF binding protein IGFBP1, a secreted modulator of IGF function. A number of the anatomical characteristics of Sirt1-null mice closely resemble those of transgenic mice overexpressing IGFBP1. Our data suggest that Sirt1 is part of a regulatory loop that limits the production of IGFBP1 thereby modulating IGF signaling.

Roles of insulin-like growth factor (IGF) binding proteins in regulating IGF actions

The insulin-like growth factor (IGF) system is an evolutionarily conserved signaling pathway that is composed of two IGF ligands, two IGF receptors, and six IGF binding proteins. Studies in a variety of species suggest that the IGF signaling system plays a fundamental role in regulating embryonic growth and differentiation as well as in maintaining homeostasis in the adults. In extracellular fluids, IGFs are present in a complex with an IGF-binding protein (IGFBP). These IGFBPs are traditionally thought to function as carrier proteins and regulate circulating IGF turnover, transport, and distribution. Locally expressed IGFBPs can also inhibit and/or potentiate IGF activities. Recent studies have shown that some IGFBPs, in particular IGFBP-3 and -5, possess intrinsic biological activities and can act through IGF-independent mechanisms. In this article, we provide a brief overview of our current understanding of the IGF signaling system with particular reference to IGFBPs.

The Loss of Glypican-3 Induces Alterations in Wnt Signaling

Loss-of-function mutations of the GPC3 gene are the cause of the human Simpson-Golabi-Behmel syndrome. Based on the overgrowth phenotype of the Simpson-Golabi-Behmel syndrome patients and the key role played by the insulin-like growth factor (IGF) signaling system in regulating embryonic growth, it was speculated that GPC3 regulates IGF signaling. In order to test the validity of this hypothesis, we mated GPC3 knockout mice with insulin receptor substrate-1 (IRS-1) nullizygous mice. We found that GPC3 regulates organism growth independent of IRS-1, suggesting that GPC3 does not modulate IGF signaling. Instead, we found that GPC3 knockout mice exhibit alterations in the Wnt signaling pathway, which is also associated with the regulation of cell proliferation. In particular, the loss of GPC3 led to the inhibition of the non-canonical Wnt/JNK signaling pathway, while concomitantly causing the activation of canonical Wnt/beta-catenin signaling. These in vivo findings were confirmed in vitro upon the ectopic overexpression of GPC3 in mesothelioma cells. In these cells, the GPC3-induced increase in JNK activity was associated with an enhanced response to Wnt5a. Most interestingly, the heparan sulfate chains of GPC3 were not required for its stimulatory activity on Wnt5a signaling and for the formation of GPC3-Wnt5a complexes. We propose that at least in some cell types GPC3 serves as a selective regulator of Wnt signaling, by potentiating non-canonical Wnt signaling, while inhibiting the canonical Wnt signaling pathway.

Effects of Mutations in the Insulin-like Growth Factor Signaling System on Embryonic Pancreas Development and β-Cell Compensation to Insulin Resistance

Insulin and insulin-like growth factors (IGF) play overlapping and complementary roles in pancreatic beta-cell function and peripheral metabolism. In this study, we have analyzed mice bearing loss-of-function mutations of the insulin/IGF signaling systems. Combined inactivation of insulin receptor (Insr) and Igf1 receptor (Igf1r), but not of either receptor alone, resulted in a 90% decrease in the size of the exocrine pancreas, because of decreased cellular proliferation. In contrast to the findings in the exocrine compartment, endocrine alpha- and beta-cell development was unperturbed. Combined ablation of Igf1 and Igf2, the ligands for these two receptors, resulted in an identical phenotype. We also examined the effect of heterozygous null Igf1r mutations on glucose homeostasis in adult mice. Igf1r haploinsufficiency did not affect insulin action and compensatory beta-cell growth in insulin-resistant mice with combined Insr and Igf1r heterozygous null mutations, resulting in a considerably milder phenotype than combined haploinsufficiency for Insr and its main signaling substrates, Irs1 and Irs2. We conclude that Igf1r and Insr are required for embryonic development of the exocrine but not of the endocrine pancreas and that defects of Igf1r do not alter glucose homeostasis as long as the insulin receptor system remains intact.

Complementary expression of IGF-II and IGFBP-5 during anterior pituitary development.

The specification of the five individual hormone-secreting cell types in the anterior pituitary requires a series of sequential cell fate decisions. We have immortalized cells at several stages along this pathway of pituitary differentiation. Here, we present analysis of differences in gene expression between an anterior pituitary precursor cell line, alphaT1-1, and an immature gonadotrope cell line, alphaT3-1, identified by using cDNA subtraction. Messenger RNA expression of members of the insulin-like growth factor signaling system, IGF-II and IGFBP-5, was found in the alphaT1-1 precursor cell line, but not in the more differentiated cell line, alphaT3-1. This inferred stage specificity was confirmed in the mouse embryo by using in situ hybridization on embryonic days e10.5 through e18.5. Expression of IGF-II and IGFBP-5 mRNAs was both temporally and spatially regulated during pituitary development. IGF-II was highly expressed in the epithelium surrounding Rathke's pouch at e10.5, while IGFBP-5 expression was restricted to the adjacent oral epithelium. At e11.5 (represented by alphaT1-1), IGF-II was expressed throughout the pouch, but was coexpressed with IGFBP-5 and alpha-subunit in the ventral portion of the pouch epithelium. On e12.5, the two mRNAs were expressed in opposing dorsoventral (IGF-II) and ventrodorsal (IGFBP-5) patterns, with IGF-II excluded from the rostral, alpha-subunit-expressing region. A decrease of both mRNAs was observed at e14.5 (equivalent to alphaT3-1), with IGF-II levels low and IGFBP-5 concentrated in the anterior pituitary rostral tip. These findings suggest that the timing of IGF-II expression and regulation of its accessibility by IGFBP-5 may play a role in anterior pituitary differentiation, survival, and/or proliferation.

Expression of components of the IGF signalling system in childhood acute lymphoblastic leukaemia

Background: Alterations in the insulin-like growth factor (IGF) system have been reported for different tumours. They are of particular interest in the search for new prognostic and therapeutic approaches in...

The insulin-like growth factor signaling system and ALS neurotrophic factor treatment strategies

Because of its multi-faceted potential as a neurotrophic factor, insulin-like growth factor I (IGF-I) has been given to hundreds of ALS patients world-wide. Unlike some patients with post-polio syndrome and fragile elderly males, it is unclear whether any of these patients possess disturbances in IGF signaling. We found that about 25% of ALS patients in a controlled trial of human growth hormone ( hGH) had lower or higher than normal IGF-I serum levels. Many ALS patients do have some of the characteristics of type II diabetes mellitus, where IGF-I therapy is also under way. In addition, in type I diabetes significant increase in a circulating molecule that binds IGF-I, IGF-I binding protein 1 (IGFBP-1), occurs along with reduced IGF-I, when neuropathie complications are prominent. We have studied the response of IGFBPs in ALS patients to subcutaneous rhIGF-I and found transient induction of IGFBP-1. Studies related to the IGFBPs have not been done in familial ALS (FALS) patients. However, the gene for another IGFBP, BP-2, co-localizes with the gene for juvenile ALS (ALSJ) on chromosome 2. IGF-I has been given to several models of motor neuron degeneration in the mouse, including motor neuron disease and wobbler, with beneficial effects. However, it is also not known whether any accepted genetic mouse model of motor neuron degeneration possesses any disturbance in the IGF signaling system.

The role of growth factors in the suppression of active cell death in the prostate: an hypothesis.

Regression of the rat ventral prostate occurs when the level of 5 alpha-dihydrotestosterone, the trophic hormone, drops below the threshold required to suppress apoptosis. The induction of apoptosis in the ventral prostate is accompanied by the increase in the steady-state level of a number of mRNAs coding for proteins that are involved in the latter stages of apoptosis and thus represent secondary thanatogens. These include proteases (cathepsins, plasminogen activators, and collagenase), clusterin, poly(ADP)ribose polymerase, tenascin, and several unidentified genes, as well as several RNases and the classical Ca2+,Mg(2+)-dependent endonuclease. In addition, insulin-like growth-factor-binding protein 5 (IGFBP-5) is induced de novo. We propose that IGFBP-5 may serve to trigger the apoptotic process through the attenuation of the insulin-like growth factor signalling system (which is necessary for cell survival), and as such, represents a primary thanatogen in the prostate.