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)

Follicles from the hen ovary that have been selected into the preovulatory hierarchy are committed to ovulation and rarely become atretic under normal physiological conditions. In part, this is attributed to the resistance of the granulosa layer to apoptosis. The present studies were conducted to evaluate the role of the phosphatidylinositol (PI) 3-kinase/Akt signaling pathway in hen granulosa cell survival and, by implication, follicle viability. Cloning of the chicken akt2 homologue revealed a high degree of amino acid homology to its mammalian counterparts within the catalytic domain, plus complete conservation of the putative Thr(308) and Ser(474) phosphorylation sites. Treatment of granulosa cells from the three largest preovulatory follicles with insulin-like growth factor (IGF)-I and, to a lesser extent, transforming growth factor (TGF)-alpha induces rapid phosphorylation of Akt, and such phosphorylation is effectively blocked by the PI 3-kinase-inhibitor LY294006. Serum withdrawal from cultured cells for 33-44 h initiates oligonucleosome formation, an indicator of apoptotic cell death, whereas cotreatment with IGF-I prevents this effect. Moreover, treatment of cultured cells for 20 h with LY294006 induces apoptosis. The potential for nonspecific cell toxicity following LY294006 treatment is considered unlikely because of the ability of either LH or 8-bromo cAMP cotreatment to block LY294006-induced cell death. Finally, both IGF-I and TGF-alpha also activate mitogen-activated protein (MAP) kinase signaling, at least in part, through the phosphorylation of ERK: However, treatment with neither U0126 nor PD98059 (inhibitors of MAP kinase kinase) induced cell death in cultured granulosa cells, despite the ability of each inhibitor to effectively block Erk phosphorylation. Taken together, these results provide evidence for a role of the Akt signaling pathway in promoting cell survival within the preovulatory follicle granulosa layer. In addition, the data indicate the importance of an alternative survival pathway mediated via gonadotropins and protein kinase A independent of Akt signaling.
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PMID:Activation of the Akt/protein kinase B signaling pathway is associated with granulosa cell survival. 1131 65

The signal transduction pathways that mediate GH-dependent regulation of IGF-I gene expression remain poorly defined. To establish a GH-responsive in vitro model system to study the effect of GH on the expression of the endogenous IGF-I gene, primary hepatocytes from adult male rats were prepared. These cells expressed both the GH receptor and the IGF-I gene, as demonstrated using a ribonuclease protection assay. Western blot analyses using antibodies directed against the phosphorylated forms of the ERKs, signal transducer and activator of transcription-5, and Akt/protein kinase B, a protein kinase that is downstream of PI3K, demonstrated GH-dependent phosphorylation of these signaling molecules. These signaling molecules are components of the major signal transduction pathways that are activated by GH. To determine whether GH-responsive IGF-I gene expression could be demonstrated in these cells, hepatocytes were treated without or with 50 ng/ml GH for 3--48 h. IGF-I mRNA levels increased within 3 h, and a maximal 2.2-fold increase was observed after 24 h of GH treatment. To determine whether ERK activation contributes to GH-induced IGF-I gene expression, hepatocytes were treated for 12 h without or with 50 ng/ml GH and 50 microM PD98059, an inhibitor of MAPK kinase-1 and -2. Treatment with PD98059 did not have a significant effect on GH-induced IGF-I gene expression. Similar studies were performed using 50 microM LY 294002, an inhibitor of PI3K. These studies demonstrated that treatment with LY 294002 completely abrogated GH-induced IGF-I gene expression. In contrast, PI3K-specific doses of another inhibitor of PI3K, wortmannin, failed to inhibit the GH-induced increase in IGF-I mRNA levels. In summary, rat hepatocytes in primary culture provide a good model system to study GH-induced IGF-I gene expression, and the results of these studies suggest that a signaling pathway inhibited by LY 294002, possibly a PI3K-dependent pathway, is important for GH-stimulated IGF-I gene expression in hepatocytes.
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PMID:LY 294002, an inhibitor of phosphatidylinositol 3-kinase, inhibits GH-mediated expression of the IGF-I gene in rat hepatocytes. 1151 77

The underlying specificity of the interaction between insulin-like growth factor-II (IGF-II) and mammalian Type 2 insulin-like growth factor/cation-independent mannose 6 phosphate receptor (IGF2R) is not understood. We have mutated residues A54 and L55 of IGF-II in the second A domain helix to arginine (found in the corresponding positions of IGF-I) and measured IGF2R binding. There is a 4- and 3.3-fold difference in dissociation constants for A54R IGF-II and L55R IGF-II, respectively, and a 6.6-fold difference for A54R L55R IGF-II compared with IGF-II as measured by BlAcore analysis using purified rat IGF2R. This is also confirmed using cross-linking and soluble rat placental membrane receptor binding assays. Binding to the type I IGF receptor (IGF1R) and IGF binding protein-2 (IGFBP-2) is not altered. We can, therefore, conclude that residues at positions 54 and 55 in IGF-II are important for and equally contribute to IGF2R binding.
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PMID:Contribution of residues A54 and L55 of the human insulin-like growth factor-II (IGF-II) A domain to Type 2 IGF receptor binding specificity. 1181 90

During the development of skeletal muscle, myoblasts withdraw from the cell cycle and differentiate into myotubes. The insulin-like growth factors IGF-I and IGF-II, through their cognate tyrosine kinase receptor (IGF-I receptor), are known to play a role in this process. After withdrawal of myoblasts from the cell cycle, IGF-I promotes muscle differentiation by inducing the expression or activity of myogenic regulatory factors (MyoD, myogenin) and effectors (p21). However, little is known about the intracellular mechanisms by which the IGF-I system regulates these factors during the process of myogenesis. Here we show that MKR mice, which express a dominant negative IGF-I receptor specifically in skeletal muscle, have marked muscle hypoplasia from birth to 3 weeks of age. This hypoplasia occurs concomitantly with a decrease in ERK immunoreactivity levels and decreases in MyoD and myogenin expression. BrdU immunocytochemistry showed a compensatory hyperplasia as MKR mice grew to adulthood. Interestingly, hyperplasia occurred concomitantly with an increase in p38, MyoD, myogenin, and p21 immunoreactivity levels, as well as a decrease in Twist levels. These findings suggest that regulation of these cellular elements by IGF-I may play a role in the development and differentiation of skeletal muscle in vivo.
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PMID:Muscle-specific inactivation of the IGF-I receptor induces compensatory hyperplasia in skeletal muscle. 1182 94

Insulin-like growth factor (IGF) binding to the type 1 IGF receptor (IGF1R) elicits mitogenic effects, promotion of differentiation and protection from apoptosis. This study has systematically measured IGF1R binding affinities of IGF-I, IGF-II and 14 IGF analogues to a recombinant high-affinity form of the IGF1R using BIAcore technology. The analogues assessed could be divided into two groups: (a) those designed to investigate binding of IGF-binding protein, which exhibited IGF1R-binding affinities similar to those of IGF-I or IGF-II; (b) those generated to probe IGF1R interactions with greatly reduced IGF1R-binding affinities. The relative binding affinities of IGF-I analogues and IGF-I for the IGF1R determined by BIAcore analysis agreed closely with existing data from receptor-binding assays using cells or tissue membranes, demonstrating that BIAcore technology is a powerful tool for measuring affinities of IGFs for IGF1R. In parallel studies, IGF1R-binding affinities were related to ability to protect against serum withdrawal-induced apoptosis in three different assays including Hoechst 33258 staining, cell survival, and DNA fragmentation assays using the rat pheochromocytoma cell line, PC12. In this model system, IGF-I and IGF-II at low nanomolar concentrations are able to prevent apoptosis completely. We conclude that ability to protect against apoptosis is directly related to ability to bind the IGF1R.
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PMID:Characteristics of binding of insulin-like growth factor (IGF)-I and IGF-II analogues to the type 1 IGF receptor determined by BIAcore analysis. 1184 98

Little is known regarding hepatic insulin-like growth factor-1 IGF-I signaling with aging despite the observation that other tissues demonstrate resistance to IGF-I with aging and declines in liver mass accompany aging. Our aim was to determine if the IGF-I-induced signaling process changes with aging. Young (5 months) and old (24 months) C57BL/6 mice hepatic tissues and blood samples were taken 20 min after an intraperitoneal injection of desIGF-I. Age had no significant effect on plasma glucose, insulin and total IGF-I levels. IRS-1 protein was significantly decreased (33%) with aging. Basal phosphorylation of IRS-1, PKB and ERK were unaffected whereas basal phosphorylation of CREB and FKHR were significantly increased (37 and 33%, respectively) with aging. desIGF-I caused a significant decrease in plasma glucose concentrations in both young (53%) and old (44%) mice. desIGF-I administration significantly increased the phosphorylation of IRS-1 in both young (104%) and old (89%) hepatic tissues. Similarly, the phosphorylation of PKB was dramatically enhanced in both young (527%) and old (350%) hepatic tissues after desIGF-I stimulation. By contrast, desIGF-I administration had no significant effects on the phosphorylation of ERK and phosphorylation of transcription factors CREB and FKHR in both young and old hepatic tissues. These data suggest that aging dose not impair IGF-I signaling in hepatic tissues.
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PMID:Effects of aging on hepatic IGF-I signaling. 1185 24

To investigate the occurrence of components of the insulin-like growth factor (IGF) system during the resorption process of shedding human deciduous teeth, we investigated sections of 13 decalcified and paraffin-embedded deciduous teeth immunohistochemically with antibodies against IGF-I and -II, six IGF binding proteins (IGFBPs 1-6) and the IGF receptors IGF1R and IGF2R. The teeth were in different stages of resorption and all showed reparative cementum formation. It was found that acellular extrinsic fiber cementum, reversal lines and reparative cellular intrinsic fiber cementum were immunoreactive for both IGFs and various IGFBPs. Therefore, in human deciduous teeth, all subgroups of cementum, but not dentine, may represent sources of components of the IGF system. Odontoclasts did not carry IGFs or the IGF1R, but IGFBPs and the IGF2R. Therefore, these cells, in contrast to osteoclasts, may not respond to IGFs, but may be involved in the release and sequestration of IGFs from cementum during the resorption process. In contrast to odontoclasts, cementoblasts and periodontal ligament (PDL) fibroblasts carried IGF1R. The influence of the IGF system on the function of these cells with respect to periodontal matrix turnover and cementogenesis is discussed. On the behalf of the IGFBP immunoreactivities found, the PDL extracellular matrix can be considered to be a reservoir for IGF system components, where binding proteins may regulate IGF distribution and activity.
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PMID:Immunohistochemical localization of components of the insulin-like growth factor-system in human deciduous teeth. 1191 73

Hepatocellular carcinoma (HCC) is a common malignancy, but treatment outcomes have generally remained poor. Specific factors important for the pathogenesis of HCC are incompletely understood. Insulin-like growth factors (IGFs) are potent autocrine and paracrine mitogens for liver cancer cell proliferation, and their bioactivity is reduced by IGF-binding protein 3 (IGFBP-3). In the present study, we report that IGFBP-3 protein levels were either undetectable (28.5%) or low (71.5%) in human HCC samples examined compared with matched non-neoplastic liver tissue by Western blotting. IGFBP-3 was localized to nontumor liver cells by immunohistochemistry with greater immunointensity than neoplastic liver cells. Levels of type I receptor (IGF-IR) were found to be low in approximately 39% of human HCC samples examined compared with matched nontumor tissues. IGF-II was overexpressed in 32%, whereas IGF-I expression was decreased in 100% of HCC samples. In vitro studies revealed that IGF-I and IGF-II induced HepG2 cell proliferation in a dose-dependent manner. Treatment of HepG2 cells with either human recombinant IGFBP-3 (hrIGFBP-3) or IGF-II antibody led to a significant reduction in cell proliferation. Cotreating these cells with hrIGFBP-3 significantly attenuated the mitogenic activity of IGF-I. IGF-I-induced phosphorylation of IGF-IR beta subunit, IRS-1, mitogen-activated protein kinase, Elk-1, and Akt-1 as well as phosphatidylinositol 3'-kinase activity was significantly attenuated when hepG2 cells were pretreated with hrIGFBP-3. Our data indicate that loss of autocrine/paracrine IGFBP-3 loops may lead to HCC tumor growth and suggest that modulating production of the IGFs, IGFBP-3, and IGF-IR may represent a novel approach in the treatment of HCC.
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PMID:A possible role for insulin-like growth factor-binding protein-3 autocrine/paracrine loops in controlling hepatocellular carcinoma cell proliferation. 1195 12

The type 1 insulin-like growth factor receptor (IGF1R) mediates tumor cell growth, adhesion, and protection from apoptosis. High plasma IGF-I levels predispose to prostate cancer, but there is no consensus regarding IGF1R expression in primary and metastatic prostate cancer. Recent studies in a human cell line and a mouse model suggest that metastatic prostate cancer cell detachment may be favored by impairing cadherin function via loss of expression of insulin receptor substrate-1 (IRS-1), the principal IGF1R docking molecule. This may be accompanied by PTEN mutation, reactivating a key antiapoptotic pathway, and by IGF1R down-regulation to prevent Shc-mediated differentiation. We studied IGF1R expression in 54 samples of primary prostate tissue including 44 archival and 10 prospectively collected biopsies. We performed semiquantitative immunostaining for the IGF1R, IRS-1, and PTEN, and in situ hybridization for IGF1R. The IGF1R was significantly up-regulated at the protein and mRNA level in primary prostate cancer compared with benign prostatic epithelium. There was a trend toward increased expression of IRS-1 in the malignant biopsies. We also measured IGF1R, IRS-1, and PTEN expression in 12 paired biopsies of primary prostate cancer and subsequent bone metastases. In four cases, IGF1R and IRS-1 levels were lower in the metastases than in the primary tumors. Three of these metastases also lacked significant PTEN staining, compatible with findings in the model systems described above. However, this pattern was relatively uncommon, and 8 of 12 cases expressed detectable IGF1R and IRS-1 in both primary and metastatic biopsies. These findings challenge earlier reports of IGF1R down-regulation in metastatic disease and reinforce the importance of the IGF1R in prostate cancer biology.
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PMID:Expression of the type 1 insulin-like growth factor receptor is up-regulated in primary prostate cancer and commonly persists in metastatic disease. 1201 76

Genetic engineering in mice has proven to be a powerful tool for studying the specificity, complementarity and redundancy in the signalling cascades by altering the structure or expression of a single gene or a set of genes, from the ligands themselves to the specific receptors to the downstream signallingplayers. These models have provided a wealth of information about the effects of a number of oncogenes and growth factors. Transgenic and gene-targeted mouse lines have been used extensively to study the function of the EGFR and its ligands, insulin-like growth factor (IGF), their receptors and binding proteins. This mini-review highlights some of the major recent findings pertinent to the EGF and IGF-I/IGFBPS transgenic model. This mini-review summarizes the current knowledge about the actions of EGF and IGFBP in vivo based on the presently established transgenic mice. We focus on results obtained from the application of transgenic and knockout models to determine the roles of EGF, IGFs in the regulation of reproduction and growth development.
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PMID:Prospects of EGF Transgenic Mice Researches. 1204 Mar 85


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