Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is evidence that growth factors, such as the insulin-like growth factors (IGFs), are involved in biological and pathological processes in oro-dento-facial tissues. To investigate their roles in tooth movement, root resorption, and repair, the occurrence of components of the IGF system, including the ligands IGF-I and -II, the IGF receptor 1 (IGF1R) and six IGF-binding proteins (IGFBP-1 to -6), was investigated by immunohistochemistry on sections from rat maxillae where the first molar had been moved mesially by means of an orthodontic appliance for 9 d to induce root resorption. After force deactivation on day 0, early repair was studied after a further 5, 7, 10, 12, 14, and 17 d. The immunostaining pattern in the periodontal ligament, cementum, and bone of control animals showed similarities known from studies in human teeth. Increased immunostaining for nearly all components in pressure sides and resorption lacunae indicated an involvement in resorption processes and clastic activities. During early stages of repair, the occurrence of several components (e.g. IGF-II, IGFBP-5 or -6) within lacunae and in cementoblasts showed an involvement in the resorption-repair sequence, which is considered to be a coupling process as known from bone.
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PMID:Insulin-like growth factor system components in the periodontium during tooth root resorption and early repair processes in the rat. 1691 Nov 3

Increased fetal lung expansion induces lung growth, cell differentiation and extracellular matrix remodelling, although the mechanisms involved are unknown. Platelet-derived growth factor (PDGF)-B, vascular endothelial growth factor (VEGF) and insulin-like growth factor (IGF)-II are mitogens activating the mitogen-activated protein kinase (MAPK) pathway, whereas transforming growth factor (TGF)-beta1 induces differentiation and extracellular matrix remodelling. In the present study, we investigated the mRNA levels of PDGF-B, VEGF, IGF-II and TGF-beta1, as well as active MAPK levels, during increased fetal lung expansion induced by tracheal obstruction (TO) in sheep for 0 (controls), 36 h or 2, 4, or 10 days (n = 5 in each group). The 3.7-kb VEGF transcript increased by 30% (P < 0.05) at 36 h TO. The expression of PDGF-B decreased by approximately 25% (P < 0.01) at 2-10 days TO. In contrast, TGF-beta1 mRNA increased by 96% (P < 0.05) at 10 days TO, when bioactive TGF-beta1 decreased by 55% (P < 0.05). Insulin-like growth factor-II mRNA tended to increase at 10 days TO (37% above controls; P = 0.07), whereas mRNA for its receptor, IGF1R, was reduced by TO. There was no change in active MAPK levels preceding or at the time of a TO-induced 800% increase in cell proliferation. We conclude that VEGF is likely to promote expansion-induced endothelial cell proliferation, but the mechanisms underlying expansion-induced proliferation of fibroblasts and alveolar epithelial cells are unlikely to be mediated by increases in PDGF-B or IGF-II expression or activation of the MAPK pathway.
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PMID:Role of platelet-derived growth factor-B, vascular endothelial growth factor, insulin-like growth factor-II, mitogen-activated protein kinase and transforming growth factor-beta1 in expansion-induced lung growth in fetal sheep. 1693 May 12

Rosiglitazone (Rosi) belongs to the class of thiazolidinediones (TZDs) that are ligands for peroxisome proliferator-activated receptor gamma (PPARgamma). Stimulation of PPARgamma suppresses bone formation and enhances marrow adipogenesis. We hypothesized that activation of PPARgamma down-regulates components of the IGF regulatory system, leading to impaired osteoblast function. Rosi treatment (1 microm) of a marrow stromal cell line (UAMS-33) transfected with empty vector (U-33/c) or with PPARgamma2 (U-33/gamma2) were analyzed by microarray. Rosi reduced IGF-I, IGF-II, IGFBP-4, and the type I and II IGF receptor (IGF1R and IGF2R) expression at 72 h in U-33/gamma2 compared with U-33/c cells (P < 0.01); these findings were confirmed by RT-PCR. Rosi reduced secreted IGF-I from U-33/gamma2 cells by 75% (P < 0.05). Primary marrow stromal cells (MSCs) extracted from adult (8 months) and old (24 months) C57BL/6J (B6) mice were treated with Rosi (1 microm) for 48 h. IGF-I, IGFBP-4, and IGF1R transcripts were reduced in Rosi-treated MSCs compared with vehicle (P < 0.01) and secreted IGF-I was also suppressed (P < 0.05). B6 mice treated with Rosi (20 mg/kg.d) for short duration (i.e. 4 d), and long term (i.e. 7 wk) had reduced serum IGF-I; this was accompanied by markedly suppressed IGF-I transcripts in the liver and peripheral fat of treated animals. To determine whether Rosi affected circulating IGF-I in humans, we measured serum IGF-I, IGFBP-2, and IGFBP-3 at four time points in 50 postmenopausal women randomized to either Rosi (8 mg/d) or placebo. Rosi-treated subjects had significantly lower IGF-I at 8 wk than baseline (-25%, P < 0.05), and at 16 wk their levels were reduced 14% vs. placebo (P = 0.15). We conclude that Rosi suppresses IGF-I expression in bone and liver; these changes could affect skeletal acquisition through endocrine and paracrine pathways.
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PMID:Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by rosiglitazone suppresses components of the insulin-like growth factor regulatory system in vitro and in vivo. 1712 83

The liver is a major metabolic and endocrine organ in growing neonates, but the extent to which its hormone receptor (R) sensitivity is potentially determined by maternal parity and the mother's nutritional environment is unknown. This was therefore investigated by sampling livers from postnatal sheep born to nulliparous or multiparous mothers. Offspring were sampled 1 or 30 days after birth from mothers consuming either 100 or 50% [i.e., nutrient-restricted (NR) group] of total metabolizable energy requirements from 110 days gestation to term ( approximately 147 days). Regardless of maternal diet, offspring of nulliparous mothers were lighter at birth and had smaller livers. By 1 mo of age, they exhibited catch-up growth, an adaptation not seen when mothers were NR, but they retained their lighter livers. At both sampling ages, livers from offspring born to nulliparous mothers exhibited increased mRNA abundance for growth hormone (GH) receptor, IGF-IR, plus hepatocyte growth factor (HGF); and at day 1 only IGF-I, but not IGF-IIR mRNA was decreased. In addition, mRNA for IGF-II, the HGFR, c-Met, and Bax were persistently reduced in these offspring. Effects of parity were largely unaffected by maternal nutrient restriction. Maternal parity therefore has a substantial effect on liver size during postnatal development and its receptor population that is not dependent on maternal diet. First-born offspring appear to exhibit a resetting of the endocrine control of hepatic growth within the HGF and GH-IGF axis, which could have later consequences after their growth has caught up.
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PMID:Effects of maternal parity and late gestational nutrition on mRNA abundance for growth factors in the liver of postnatal sheep. 1720 89

The type 1 IGF receptor (IGF1R) is a transmembrane tyrosine kinase that is frequently overexpressed by tumours, and mediates proliferation and apoptosis protection. IGF signalling also influences hypoxia signalling, protease secretion, tumour cell motility and adhesion, and thus can affect the propensity for invasion and metastasis. Therefore, the IGF1R is now an attractive anti-cancer treatment target. This review outlines the effects of IGF1R activation in tumour cells, and will describe the strategies that are available to block IGF signalling, both as investigational tools and as novel anti-cancer therapeutics. Design of specific IGF1R inhibitors has been problematic due to close homology with the insulin receptor, but recently it has proved possible to design selective IGF1R inhibitors. These compounds and IGF1R antibodies are showing promise in preclinical models of human cancer, and several agents are now in early phase clinical trials. Both classes of agents affect insulin receptor signalling, either by direct kinase inhibition or antibody-induced insulin receptor downregulation. This effect may lead to clinical toxicity, but could be therapeutically beneficial in blocking signalling via variant insulin receptors capable of a mitogenic response to IGF-II. Specificity for IGF1R targeting can be achieved by antisense and siRNA-mediated IGF1R downregulation; these approaches have undoubted utility as research tools, and may in future generate nucleic-acid-based therapeutics. It will be important to use data from preclinical and early clinical trials to establish the molecular correlates of sensitivity to IGF1R blockade, and the optimum means of combining this new approach with standard treatment modalities.
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PMID:IGF1R signalling and its inhibition. 1725 57

The insulin-like growth factor (IGF) signaling system plays indispensable roles in pre- and post-natal brain growth and development. A large body of studies using both in vivo null mutant and transgenic mice and in vitro neuronal culture techniques indicate that IGF-I acts directly on the brain while IGF-II effects are mediated to a large extent by IGF-II control of placental growth. It appears that all of the mechanisms, except migration, that are involved in normal brain development, e.g., proliferation, apoptosis, maturation and differentiation, are influenced by IGF-I. While IGF system members are produced in the brain, recent reports in post-natal animals indicate that normal brain health and function are dependent upon transfer of circulating IGF-I from the liver and its transfer across the blood brain barrier. Data showing that this phenomenon applies to pre-natal brain growth and development would make an important contribution to fetal physiology. A number of kinase pathways are able to participate in IGF signaling in brain with respect to nutrient restriction; among the most important are the PI3K/AKT, Ras-Raf-MEK-ERK and mTOR-nutrient sensing pathways. Both maternal and fetal IGF-I peripheral plasma concentrations are greatly reduced in nutrient restriction while IGF-II does not appear to be affected. Nutrient restriction also affects IGF binding protein concentrations while effects on the IGF-I receptor appear to vary with the paradigm. Studies on the effects of nutrient restriction on the fetal primate brain in relation to activity of the IGF system are needed to determine the applicability of rodent studies to humans.
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PMID:The insulin-like growth factor system and the fetal brain: effects of poor maternal nutrition. 1765 68

The ability of plant lectins to modify the interactions of the insulin receptor (IR) and insulin-like growth factor (IGF) receptors (IGFRs) with their ligands was investigated. The lectins profoundly affected the competition-binding curves for (125)I-labelled IGF-I and insulin, causing an increase in the affinity of placental IGF1R and IR towards their ligands. This increment was of such a magnitude that it could affect the receptors' specificity towards these ligands. The lower the ligand concentration, the greater was the lectin-induced affinity shift, which suggests potential physiological significance of the effect. The affinity modulation occurred in a lectin-specific and dose-dependent manner. In contrast to IGF1R and IR, the binding of (125)I-labelled IGF-II to its receptors resisted lectin modulation. Here we provide evidence of the possibility of external modulation of the affinity of placental IGF1R and IR via interactions of the receptors' carbohydrate moieties with lectins. The existence of modulators that would selectively inhibit or enhance the binding of IGFs or insulin to their corresponding receptors may have important implications for placental cell responses to these molecules.
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PMID:Affinity modulation of human placental insulin and insulin-like growth factor receptors by lectins. 1831 33

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system neoplasm that usually affects infants and young children. In this report, we describe culture conditions that enabled the sustained growth of tumor cells obtained from the cerebrospinal fluid (CSF) of an infant with AT/RT. These cells retained the morphological and biomarker characteristics of the original tumor. A screening of receptor tyrosine kinases identified the presence of phosphorylated ErbB4, Insulin-R, PDGFR and IGF-IR, which appear to depend on Hsp90 to maintain their active form. IGF-IR activity is consistent with data from other established AT/RT cell lines. Inhibition of IGF-IR by the small molecular weight inhibitor AEW541 led to growth suppression of cultured AT/RT cells. In addition, neutralizing antibodies to IGF-II also inhibited the growth of these cells suggesting a potential autocrine function for this cytokine. We also compared cultured AT/RT cells to established cell lines to identify consistent drug sensitivity patterns among these cells. In addition to previously described cell lines and xenograft models, continuous culture of CSF derived cells may also provide an effective way to study the biology of AT/RT and to identify potential targets for future therapeutics for this tumor.
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PMID:Establishment of atypical-teratoid/rhabdoid tumor (AT/RT) cell cultures from disseminated CSF cells: a model to elucidate biology and potential targeted therapeutics. 1865 Nov 3

Our previous studies found that insulin-like growth factor-I receptor (IGF1R) signaling blockade caused cardiac hypertrophy, and that apoptosis is required for upregulating the IGF-II and the IGF-II/ mannose 6-phosphate receptor (IGF2R) gene. However, the role of IGF-II in the regulation of cell apoptosis through IGF2R is little known. In this study, we hypothesized that IGF-II may induce cell apoptosis through IGF2R but is dependent on IGF1R activity. Western blots and TUNEL assay revealed that in the presence of IGF1R, exogenous IGF-II acts, like IGF-I, would increase phospho-Akt through IGF1R, but does not affect the caspase 3 activation and apoptotic induction in H9c2 cardiomyoblast cells. Conversely, AG1024, an inhibitor of IGF1R activity, causes cell apoptosis, and the treatment with IGF-II further enhances this process, implying that it occurs through IGF2R. Moreover, immunoprecipitation assay revealed that treatment with IGF-II could enhance the interaction of IGF2R with Galphai and Galphaq but reduce its binding with Galphas, resulting in the reduction of phospho-PKA and the activation of PLC-beta. Taken together, these data provide new insight into the dual role of IGF-II in the control of IGF1R dependent cell apoptosis and involved activation of IGF2R signaling. Improving IGF1R activity and suppressing IGF2R may be a good strategy to prevent the progression of heart disease with cardiomyocyte apoptosis.
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PMID:Enhancement of AG1024-induced H9c2 cardiomyoblast cell apoptosis via the interaction of IGF2R with Galpha proteins and its downstream PKA and PLC-beta modulators by IGF-II. 1976 51

In humans, a direct relationship between IGF-I cord blood levels and birth weight has been demonstrated. To determine the placental IGF-I, IGF-II and IGF-IR mRNA and protein contents in full-term pregnancies from appropriate for gestational age (AGA), small for gestational age (SGA) and large for gestational age (LGA) newborns, we studied the placentas from 35 AGA, 30 SGA and 28 LGA pregnancies. The IGF-I, IGF-II and IGF-I receptor (IGF-IR) placental mRNA and protein contents were determined in the basal and chorionic plates of the placenta. IGF1 and IGF1R mRNA was higher in SGA compared to AGA and LGA placentas and lower in LGA compared with AGA placentas. In addition, a higher protein content of IGF-I and IGF-IR was observed in SGA compared with AGA and LGA placentas and lower contents in LGA compared with AGA placentas. These results suggest that the higher IGF-I and IGF-IR contents observed in SGA placentas and the lower contents observed in LGA placentas compared with AGA placentas may be influencing human fetal growth.
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PMID:Expression and protein content of IGF-I and IGF-I receptor in placentas from small, adequate and large for gestational age newborns. 2038 1


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