Expression of the IGFBP-2 gene in post-implantation rat embryos

Development ◽  
1992 ◽  
Vol 114 (1) ◽  
pp. 59-66 ◽  
Author(s):  
T.L. Wood ◽  
R.D. Streck ◽  
J.E. Pintar
Keyword(s):  
Cell Types ◽  
Tail Bud ◽  
Igf Binding Proteins ◽  
Surface Ectoderm ◽  
Genes Encoding ◽  
Mantle Layer ◽  
Igf Binding ◽  
Post Implantation

The insulin-like growth factors (IGFs) stimulate mitogenesis in a variety of cell types both in vitro and in vivo. These effects are mediated by both IGF receptors and a family of IGF binding proteins (IGFBPs), which are found complexed with the IGFs in serum and tissue fluids. Here we compare the sites of expression during early rat embryogenesis of the genes encoding the RGD-containing IGF binding protein IGFBP-2 and IGF-II. At all ages from early post-implantation through mid-gestation, the expression of IGFBP-2 was highly complementary to IGF-II. IGFBP-2 mRNA was detected throughout the epiblast of the egg cylinder as early as e7, when IGF-II expression was restricted to trophectoderm and other extraembryonic cells. As gastrulation proceeded, IGFBP-2 expression ceased as IGF-II expression began in the newly formed embryonic and extra-embryonic mesoderm, but was retained in other epiblast derivatives including the surface ectoderm and neuroectoderm, throughout its rostral-caudal extent. By e10-e11, IGFBP-2 expression in neuroectoderm was restricted to the rostral brain of the primary neural tube and was found in the new population of neuroepithelium formed in the tail bud during secondary neurulation. IGFBP-2 expression remained high in the ventricular layer of the rostral brain into mid-gestation ages but decreased or disappeared as cells entered the mantle layer and began to express the neurofilament-related gene alpha-internexin. IGFBP-2 mRNA was abundant in surface ectoderm, particularly that of the branchial arches, and all ectodermal placodes.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals IGF-binding protein-4: biochemical characteristics and functional consequences

2003 ◽  
Vol 178 (2) ◽  
pp. 177-193 ◽  
Author(s):  
R Zhou ◽  
D Diehl ◽  
A Hoeflich ◽  
H Lahm ◽  
E Wolf
Keyword(s):  
Biological Fluids ◽  
Biological Significance ◽  
Structural Similarity ◽  
Cell Types ◽  
Cellular Growth ◽  
Igf Binding Proteins ◽  
Wide Range ◽  
Igf Binding

IGFs have multiple functions regarding cellular growth, survival and differentiation under different physiological and pathological conditions. IGF effects are modulated systemically and locally by six high-affinity IGF-binding proteins (IGFBP-1 to -6). Despite their structural similarity, each IGFBP has unique properties and exhibits specific functions. IGFBP-4, the smallest IGFBP, exists in both non-glycosylated and N-glycosylated forms in all biological fluids. It is expressed by a wide range of cell types and tIssues, and its expression is regulated by different mechanisms in a cell type-specific manner. IGFBP-4 binds IGF-I and IGF-II with similar affinities and inhibits their actions under almost all in vitro and in vivo conditions. In this review, we summarize the available data regarding the following aspects of IGFBP-4: genomic organization, protein structure-function relationship, expression and its regulation, as well as IGF-dependent and -independent actions. The biological significance of IGFBP-4 for reproductive physiology, bone formation, renal pathophysiology and cancer is discussed.

scholarly journals Heparin-binding mechanism of the IGF2/IGF-binding protein 2 complex

2014 ◽  
Vol 52 (3) ◽  
pp. 345-355 ◽  
Author(s):  
Jacob Lund ◽  
Mads T Søndergaard ◽  
Cheryl A Conover ◽  
Michael T Overgaard
Keyword(s):  
Bone Matrix ◽  
Receptor Activation ◽  
Heparin Binding ◽  
Igf Binding Proteins ◽  
Skeletal Mass ◽  
Igf Binding ◽  
Heparin Affinity ◽  
Positively Charged

IGF1 and IGF2 are potent stimulators of diverse cellular activities such as differentiation and mitosis. Six IGF-binding proteins (IGFBP1–IGFBP6) are primary regulators of IGF half-life and receptor availability. Generally, the binding of IGFBPs inhibits IGF receptor activation. However, it has been shown that IGFBP2 in complex with IGF2 (IGF2/IGFBP2) stimulates osteoblast function in vitro and increases skeletal mass in vivo. IGF2 binding to IGFBP2 greatly increases the affinity for 2- or 3-carbon O-sulfated glycosaminoglycans (GAGs), e.g. heparin and heparan sulfate, which is hypothesized to preferentially and specifically target the IGF2/IGFBP2 complex to the bone matrix. In order to obtain a more detailed understanding of the interactions between the IGF2/IGFBP2 complex and GAGs, we investigated heparin-binding properties of IGFBP2 and the IGF2/IGFBP2 complex in a quantitative manner. For this study, we mutated key positively charged residues within the two heparin-binding domains (HBDs) in IGFBP2 and in one potential HBD in IGF2. Using heparin affinity chromatography, we demonstrate that the two IGFBP2 HBDs contribute differentially to GAG binding in free IGFBP2 and the IGF2/IGFBP2 protein complex. Moreover, we identify a significant contribution from the HBD in IGF2 to the increased IGF2/IGFBP2 heparin affinity. Using molecular modeling, we present a novel model for the IGF2/IGFBP2 interaction with heparin where all three proposed HBDs constitute a positively charged and surface-exposed area that would serve to promote the increased heparin affinity of the complex compared with free intact IGFBP2.

Differences in the association of insulin-like growth factor-I (IGF-I) and IGF-I variants with rat, sheep, pig, human and chicken plasma-binding proteins

1994 ◽  
Vol 140 (3) ◽  
pp. 475-482 ◽  
Author(s):  
A P D Lord ◽  
S E P Bastian ◽  
L C Read ◽  
P E Walton ◽  
F J Ballard
Keyword(s):  
Binding Proteins ◽  
Rat Plasma ◽  
Size Exclusion ◽  
Free Form ◽  
Igf Binding Proteins ◽  
Igf I ◽  
Exclusion Chromatography ◽  
Igf Binding

Abstract Associations between labelled insulin-like growth factors (IGFs) and IGF-binding proteins in plasma have been compared in the rat, sheep, human, pig and chicken. The IGFs tested were recombinant human IGF-I, the truncated variant, des(1–3)IGF-I, and LR3IGF-I, an extended form that had been engineered so as to minimize interactions with IGF-binding proteins. Marked species differences were demonstrated, notably that the IGF-I variants which exhibited extremely weak binding in rat plasma bound significantly in plasma from the other species. This result was shown both by size-exclusion chromatography of labelled IGFs added to plasma, in which the extent of variant IGF-I binding decreased in the order sheep>human>pig=chicken>rat, and by competition for labelled IGF-I binding in vitro, in which the order was pig=chicken>sheep>human>rat. Notwithstanding these differences, the two IGF-I variants showed only slight between-species binding differences when tested with purified rat, sheep and human IGF-binding protein-3. Ligand blotting experiments with plasma from the five species similarly showed a consistent pattern in that IGF-I binding was much greater than des(1–3)IGF-I binding, which in turn was greater than LR3 IGF-I binding. These experiments suggest first that IGF-binding properties measured after the removal of endogenous IGFs do not always reflect the situation with untreated plasma or in vivo, and secondly, the increased potencies of des(1–3)IGF-I and LR3 IGF-I in rat growth studies that have been ascribed to higher concentrations of these peptides in the free form cannot necessarily be extended to other species. Journal of Endocrinology (1994) 140, 475–482

Activity of IGF-binding proteins in seminal plasma of bulls: Effects on fertilization capacity in vivo and in vitro

1998 ◽  
Vol 49 (1) ◽  
pp. 373
Author(s):  
G. Schmelzinger ◽  
J. Schwartz ◽  
T. Grupp ◽  
H.-D. Reichenbach ◽  
E. Wolf
Keyword(s):  
Seminal Plasma ◽  
Binding Proteins ◽  
Igf Binding Proteins ◽  
Igf Binding ◽  
Fertilization Capacity

scholarly journals Prednisolone reduces the ability of serum to activate the IGF1 receptor in vitro without affecting circulating total or free IGF1

2013 ◽  
Vol 168 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Jan Frystyk ◽  
Anders J Schou ◽  
Carsten Heuck ◽  
Henrik Vorum ◽  
Mikkel Lyngholm ◽  
...  
Keyword(s):  
Receptor Activation ◽  
Specific Cell ◽  
Serum Samples ◽  
Double Blind ◽  
Igf Binding Proteins ◽  
Activation Assay ◽  
Igf Binding ◽  
Igf1 Receptor

ObjectiveEnd-point bioassays based on thymidine or sulfate incorporation have demonstrated that glucocorticoid (GC) treatment inhibits serum IGF1 action, but the mechanism is unknown as serum IGF1 concentrations have been reported to either increase or remain unchanged.AimTo investigate whether GC treatment affects the ability of serum to activate the IGF1 receptor (IGF1R) in vitro (i.e. bioactive IGF1), using a specific cell-based IGF1 kinase receptor activation assay.Subjects and methodsTwenty children with stable asthma (age 7.7–13.8 years) treated for 1 week with 5 mg prednisolone in a randomized, double-blind, placebo-controlled crossover study. Non-fasting serum samples were collected in the afternoon after each 7-day period and assayed for bioactive IGF1, free IGF1, total IGFs, IGF-binding proteins (IGFBPs), and insulin.ResultsPrednisolone treatment reduced IGF1 bioactivity by 12.6% from 2.22±0.18 to 1.94±0.15 μg/l (P=0.01) compared with placebo. In contrast, no changes were observed for (μg/l; placebo vs prednisolone) total IGF1 (215±27 vs 212±24), free IGF1 (1.50±0.16 vs 1.43±0.17), total IGF2 (815±26 vs 800±31), IGFBP3 (3140±101 vs 3107±95), IGFBP2 (238±21 vs 220±19), IGFBP1 (32±6 vs 42±10), or IGFBP1-bound IGF1 (24±5 vs 26±7). Insulin remained unchanged as did IGFBP levels as estimated by western ligand blotting. Prednisolone had no direct effects on IGF1R phosphorylation.ConclusionsOur study gives evidence that GC treatment induces a circulating substance that is able to inhibit IGF1R activation in vitro without affecting circulating free or total IGF1. This may be one of the mechanisms by which GC inhibits IGF1 action in vivo. However, the nature of this circulating substance remains to be identified.

scholarly journals Insulin-Like Growth Factor (IGF) Binding Protein-4 Is Both a Positive and Negative Regulator of IGF Activity in Vivo

2008 ◽  
Vol 22 (5) ◽  
pp. 1213-1225 ◽  
Author(s):  
Yun Ning ◽  
Alwin G. P. Schuller ◽  
Cheryl A. Conover ◽  
John E. Pintar
Keyword(s):  
Plasma Protein ◽  
Protein A ◽  
Postnatal Growth ◽  
Negative Regulator ◽  
Igf Binding Proteins ◽  
Prenatal Growth ◽  
Igf Binding ◽  
Growth Deficit

Abstract IGFs are required for normal prenatal and postnatal growth. Although actions of IGFs can be modulated by a family of IGF-binding proteins (IGFBPs) in vitro, these studies have identified a complicated pattern of stimulatory and inhibitory IGFBP effects, so that understanding relevant aspects of IGFBP action in vivo has been limited. Here we have produced a null mutation of one specific IGFBP, IGFBP-4, which is coexpressed with IGF-II early in development. Surprisingly, mutation of IGFBP-4, believed from in vitro studies to be exclusively inhibitory, leads to a prenatal growth deficit that is apparent from the time that the IGF-II growth deficit first arises, which strongly suggests that IGFBP-4 is required for optimal IGF-II-promoted growth during fetal development. Mice encoding a mutant IGFBP-4 protease (pregnancy-associated plasma protein-A), which facilitates IGF-II release from an inactive IGF-II/IGFBP-4 complex in vitro, are even smaller than IGFBP-4 mutant mice. However, the more modest IGFBP-4 growth deficit is completely restored in double IGFBP-4/pregnancy-associated plasma protein-A-deficient mice. Taken together these results indicate not only that IGFBP-4 functions as a local reservoir to optimize IGF-II actions needed for normal embryogenesis, but also establish that IGFBP-4 proteolysis is required to activate most, if not all, IGF-II mediated growth-promoting activity.

Characterization of serum-derived and recombinant rat IGF-I and their use for measuring true concentrations of IGF-I in rat plasma

1996 ◽  
Vol 149 (3) ◽  
pp. 379-387 ◽  
Author(s):  
Z Upton ◽  
H Webb ◽  
F M Tomas ◽  
F J Ballard ◽  
G L Francis
Keyword(s):  
Rat Plasma ◽  
Reference Standards ◽  
Igf Binding Proteins ◽  
Igf I ◽  
Igf Binding ◽  
Igf Receptor

Abstract While numerous researchers have used rat models to investigate the in vivo actions of IGF-I, interpretation of the results in terms of true concentrations of rat IGF-I (rIGF-I) in plasma has been hampered by the absence of homologous reference standards. In order to overcome this we have produced recombinant rIGF-I (rrIGF-I) from Escherichia coli using procedures similar to those we have previously described for the production of other recombinant IGFs. The rrIGF-I is indistinguishable from serum-derived rIGF-I when characterized in a number of in vitro assays including ability to stimulate protein synthesis and inhibit protein degradation in cultured rat cells, as well as in interactions with the rat type-1 IGF receptor and with rat IGF-binding proteins. Moreover, both the serum-derived and the recombinant rat proteins are similar to recombinant human IGF-I (rhIGF-I) in these assays. However, differences between the human and rat IGFs are apparent when tested in immunoassays using some antibodies raised against rhIGF-I. Furthermore, the differences between rhIGF-I and rrIGF-I are even greater when rhIGF-I is used as the competing radiolabel in these assays, a situation that can lead to a two- to threefold underestimation of the actual concentration of IGF-I in rat plasma. These results indicate that, while immunoassays employing antibodies raised against rhIGF-I and rhIGF-I reference standards reliably indicate trends in IGF-I concentrations in rat plasma, the true amounts of rIGF-I present can only be assured in an assay using homologous tracer and reference peptides. Journal of Endocrinology (1996) 149, 379–387

scholarly journals PhaC and PhaR Are Required for Polyhydroxyalkanoic Acid Synthase Activity in Bacillus megaterium

2001 ◽  
Vol 183 (14) ◽  
pp. 4235-4243 ◽  
Author(s):  
Gabriel J. McCool ◽  
Maura C. Cannon
Keyword(s):  
Bacillus Megaterium ◽  
Inclusion Bodies ◽  
Active Form ◽  
Cell Types ◽  
Pha Synthase ◽  
Class Iii ◽  
Polyhydroxyalkanoic Acid ◽  
Genes Encoding

ABSTRACT Polyhydroxyalkanoic acids (PHAs) are a class of polyesters stored in inclusion bodies and found in many bacteria and in some archaea. The terminal step in the synthesis of PHA is catalyzed by PHA synthase. Genes encoding this enzyme have been cloned, and the primary sequence of the protein, PhaC, is deduced from the nucleotide sequences of more than 30 organisms. PHA synthases are grouped into three classes based on substrate range, molecular mass, and whether or not there is a requirement for phaE in addition to thephaC gene product. Here we report the results of an analysis of a PHA synthase that does not fit any of the described classes. This novel PHA synthase from Bacillus megaterium required PhaC (PhaCBm) and PhaR (PhaRBm) for activity in vivo and in vitro. PhaCBm showed greatest similarity to the PhaCs of class III in both size and sequence. Unlike those in class III, the 40-kDa PhaE was not required, and furthermore, the 22-kDa PhaRBm had no obvious homology to PhaE. Previously we showed that PhaCBm, and here we show that PhaRBm, is localized to inclusion bodies in living cells. We show that two forms of PHA synthase exist, an active form in PHA-accumulating cells and an inactive form in nonaccumulating cells. PhaC was constitutively produced in both cell types but was more susceptible to protease degradation in the latter type. Our data show that the role of PhaR is posttranscriptional and that it functions directly or indirectly with PhaCBm to produce an active PHA synthase.

scholarly journals The Role of GH/IGF Axis in Dento-Alveolar Complex from Development to Aging and Therapeutics: A Narrative Review

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1181
Author(s):  
Kouassi Armel Koffi ◽  
Sophie Doublier ◽  
Jean-Marc Ricort ◽  
Sylvie Babajko ◽  
Ali Nassif ◽  
...  
Keyword(s):  
Cell Types ◽  
Periodontal Ligament Cells ◽  
Igf Binding Proteins ◽  
Paracrine Effects ◽  
Innovative Strategies ◽  
Dental Tissues ◽  
Mineralized Tissues

The GH/IGF axis is a major regulator of bone formation and resorption and is essential to the achievement of normal skeleton growth and homeostasis. Beyond its key role in bone physiology, the GH/IGF axis has also major pleiotropic endocrine and autocrine/paracrine effects on mineralized tissues throughout life. This article aims to review the literature on GH, IGFs, IGF binding proteins, and their respective receptors in dental tissues, both epithelium (enamel) and mesenchyme (dentin, pulp, and tooth-supporting periodontium). The present review re-examines and refines the expression of the elements of the GH/IGF axis in oral tissues and their in vivo and in vitro mechanisms of action in different mineralizing cell types of the dento-alveolar complex including ameloblasts, odontoblasts, pulp cells, cementoblasts, periodontal ligament cells, and jaw osteoblasts focusing on cell-specific activities. Together, these data emphasize the determinant role of the GH/IGF axis in physiological and pathological development, morphometry, and aging of the teeth, the periodontium, and oral bones in humans, rodents, and other vertebrates. These advancements in oral biology have elicited an enormous interest among investigators to translate the fundamental discoveries on the GH/IGF axis into innovative strategies for targeted oral tissue therapies with local treatments, associated or not with materials, for orthodontics and the repair and regeneration of the dento-alveolar complex and oral bones.

Physiologic IGFBP7 levels prolong IGF1R activation in acute lymphoblastic leukemia

2021 ◽  
Vol 5 (18) ◽  
pp. 3633-3646
Author(s):  
Leonardo Luís Artico ◽  
Angelo Brunelli Albertoni Laranjeira ◽  
Livia Weijenborg Campos ◽  
Juliana Ronchi Corrêa ◽  
Priscila Pini Zenatti ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Insulin Receptor ◽  
Lymphoblastic Leukemia ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Igf Binding Proteins ◽  
Childhood All ◽  
Erk Phosphorylation

Abstract Insulin and insulin-like growth factors (IGFs) are mitogenic and prosurvival factors to many different cell types, including acute lymphoblastic leukemia (ALL). Circulating IGFs are bound by IGF binding proteins (IGFBPs) that regulate their action. IGFBP7 is an IGFBP-related protein (IGFBP-rP) that in contrast to other IGFBPs/IGFBP-rPs features higher affinity for insulin than IGFs and was shown to bind the IGF1 receptor (IGF1R) as well. The role of IGFBP7 in cancer is controversial: on some tumors, it functions as an oncogene, whereas in others, it functions as a tumor suppressor. In childhood ALL, higher IGFBP7 expression levels were associated with worse prognosis. Here we show that IGFBP7 exerts mitogenic and prosurvival autocrine effects on ALL cells that were dependent on insulin/IGF. IGFBP7 knockdown or antibody-mediated neutralization resulted in significant attenuation of ALL cell viability in vitro and leukemia progression in vivo. IGFBP7 was shown to prolong the surface retention of the IGF1R under insulin/IGF1 stimulation, resulting in sustained IGF1R, insulin receptor substrate 1 (IRS-1), protein kinase B (AKT), and extracellular signal-regulated kinase (ERK) phosphorylation. Conversely, the insulin receptor was readily internalized and dephosphorylated on insulin stimulation, despite IGFBP7 addition. The affinity of homodimeric IGF1R for insulin is reportedly >100 times lower than for IGF1. In the presence of IGFBP7, however, 25 ng/mL insulin resulted in IGF1R activation levels equivalent to that of 5 ng/mL IGF1. In conclusion, IGFBP7 plays an oncogenic role in ALL by promoting the perdurance of IGF1R at the cell surface, prolonging insulin/IGF stimulation. Preclinical data demonstrate that IGFBP7 is a valid target for antibody-based therapeutic interventions in ALL.

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