Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The Grb10 gene on chromosome 7p11.2-p12 belongs to a family of adapter proteins known to interact with a number of receptor tyrosine kinases, such as EGF, ErbB2/Her2, platelet-derived growth factor (PDGF), IGF-I receptors and vascular endothelial growth factor (VEGF) receptor, KDR (kinase insert domain containing receptor). In addition to receptor tyrosine kinases, Grb10 has also been found to interact with non-receptor tyrosine kinases such as Tec and Bcr-Abl, other cellular signaling molecules such as Raf-1, and the mitogen-activated protein (MAP) kinase, MEK. We demonstrated increased expression of Grb10 mRNA in more than one half of primary cervical squamous cell cancers (12 of 15 cases) when compared to corresponding non-cancerous uterine squamous cell tissues. In addition, immunohistochemical staining demonstrated that the Grb10 protein was prominent in the cytoplasm of cancer cells, whereas it was unreactive in the surrounding normal cervical squamous cells. In addition, its interruption by siRNA exhibited marked cell growth inhibition. These data indicate that amplification and increased expression of the Grb10 gene may play a role in the development of a portion of human cervical squamous cell cancer.
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PMID:Up-regulation of growth factor receptor-bound protein 10 in cervical squamous cell carcinoma. 1587 Sep 23

Numerous studies have described the presence of an intragonadal IGF system involved in regulation of gametogenesis in teleost fish. In the present study, the in vivo effects of estradiol-17beta (E2) and growth hormone (GH) exposure on IGF-I, IGF-II, IGF1R, and IGFBP2 gene expression in sea bream ovary were monitored by RT-PCR during prereproductive and reproductive periods. The evidence demonstrates that both hormones investigated here affect the ovarian IGF system, showing that it is not only under GH control, but also can be regulated by sexual hormones; this hormonal modulation is related to reproductive phase.
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PMID:Hormonal control of the IGF system in the sea bream ovary. 1589 Oct 51

Bone marrow stromal cells (MSC) are the major source of osteoblasts for bone remodeling and repair in postnatal animals. Rodent MSC cultured with bone morphogenetic proteins (BMPs) differentiate into osteoblasts, but most human MSC show a poor osteogenic response to BMPs. In this study we demonstrate that BMP-induced osteogenesis in poorly responsive human MSC requires modulation of ERK and phosphatidylinositol 3-kinase (PI3-K) pathways. Either treating human MSC cultures with the MAPK/ERK kinase inhibitor PD98059 or transferring them to serum-free medium with insulin or IGF-I permits BMP-dependent increases in the expression of the early osteoblast-associated genes, alkaline phosphatase and osteopontin. Increased expression of these genes in BMP-treated, serum-free cultures correlates with increased nuclear levels of activated Smads, whereas serum-free cultures of human MSC expressing constitutively active MAPK/ERK kinase show decreased expression of early osteoblast genes and decreased nuclear translocation of BMP-activated Smads. Inhibiting ERK activity in human MSC also elevates the expression of Msx2, a transcription factor that is directly regulated by Smad-binding elements in its promoter. Therefore, growth factor stimulation leading to high levels of ERK activity in human MSC results in suppressed BMP-induced transcription of several early osteoblast genes, probably because levels of BMP-activated nuclear Smads are decreased. In contrast, inhibiting the insulin/IGF-I-activated PI3-K/AKT pathway decreases BMP-induced alkaline phosphatase and osteopontin expression in serum-free cultures of human MSC, but increases BMP activation of Smads; thus, PI3-K signaling is required for BMP-induced expression of early osteoblast genes in human MSC either downstream or independent of the BMP-activated Smad signaling pathway.
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PMID:Bone morphogenetic protein regulation of early osteoblast genes in human marrow stromal cells is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling. 1590 16

We investigated parathyroid hormone (PTH)/PTH-related protein receptor (PTH1R) gene suppression induced by insulin-like growth factor (IGF)-I using a rat osteoblast-like cell line (UMR-106). Observations were made with PD98059, a specific ERK signaling pathway inhibitor, and UMR-106 cells transfected with dominant negative or constitutively active forms of MAP kinase kinase. IGF-I inhibited PTH1R gene expression via an ERK1/2 MAP kinase pathway. We cloned the 8-kb promoter region of the rat PTH1R gene and characterized the U3 promoter, a major IGF-I-responsive promoter among the two present in rat osteoblasts. The IGF-I-suppressive region was between +1 and +25, identical to the previously described PTH-suppressive region (PTHSR). Gel mobility-shift detected a specific DNA-protein complex decreased by IGF-I. Mutation involving a three base sequence (+1 to +3) among more than 3.5 kb constituting the PTH1R promoter region completely abolished IGF-I action. Thus, IGF-I signaling may act at the osteoblast exon U3 transcription initiation site to repress the transcriptional activity.
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PMID:Identification of the promoter region of the parathyroid hormone receptor gene responsible for transcriptional suppression by insulin-like growth factor-I. 1595 Sep 22

In mammary epithelial cells (MEC) TGF-beta(1) is the auto-/paracrine growth inhibitor and inducer of apoptosis and therefore is considered as an important local regulator of mammary tissue involution. However, the mechanisms of controlled TGF-beta(1) expression in the course of bovine mammary gland remodelling are still unclear. Recent study performed in this laboratory support the evidence that TGF-beta(1) expression in bovine MEC is regulated by hormones of somatotropic axis (GH, IGF-I and somatostatin). Present study was focused on the contribution of IGF-I-induced signaling pathways in anti-TGF-beta(1) and anti-apoptotic effects of IGF-I. Laser scanning cytometry was applied for the measurement of TGF-beta(1) content and apoptotic cell number in bovine BME-UV1 MEC. Involution of the bovine mammary gland in vitro was modeled by decreasing the availability of FBS for bovine MEC. Reducing FBS content in the medium from 10% to 0.5% evoked highly significant increase of TGF-beta(1) expression and increase of apoptotic cell number. IGF-I (50 ng/ml) completely abrogated FBS deficiency-induced TGF-beta(1) expression and apoptosis in bovine MEC. In order to establish which of the IGF-I signaling pathways contributed to anti-TGF-beta(1) and anti-apoptotic effects, the inhibitors of PI3-kinase - (LY 294002) and MEK- (MAPKK for ERK) (PD 098059) mediated signaling pathways were applied to our model. The results clearly showed that inhibition of PI3-K reverses the ability of IGF-I to suppress TGF-beta(1) expression and apoptosis. An inhibition of ERK1/2 pathway even potentiated inhibitory effect of IGF-I on TGF-beta(1) expression, but partially abrogated anti-apoptotic effect of IGF-I. In conclusion, the results of the study indicate that PI3-K/Akt pathway contributed significantly to the inhibition of TGF-beta(1) expression by IGF-I, whereas both PI3-K/Akt and ERK1/2 pathways are involved in the anti-apoptotic effect of IGF-I in bovine MEC.
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PMID:Dissimilar effects of LY 294002 and PD 098059 in IGF-I-mediated inhibition of TGF-beta1 expression and apoptosis in bovine mammary epithelial cells. 1607 2

In muscle, physiologic hyperinsulinemia, presumably acting on endothelial cells (ECs), dilates arterioles and regulates both total blood flow and capillary recruitment, which in turn influences glucose disposal. In cultured ECs, however, supraphysiological (e.g. >or=10 nM) insulin concentrations are typically used to study insulin receptor (IR) signaling pathways and nitric oxide generation. IGF-I receptors (IGF-IRs) are more abundant than IR in ECs, and they also respond to high concentrations of insulin. To address whether IR mediates responses to physiologic insulin stimuli, we examined the insulin concentration dependence of IR and IGF-IR-mediated insulin signaling in bovine aortic ECs (bAECs). We also assessed whether insulin/IGF-I hybrid receptors were present in bAECs. Insulin, at 100-500 pM, significantly stimulated the phosphorylation of IRbeta, Akt1, endothelial isoform of nitric oxide synthase, and ERK 1/2 but not the IGF-IRbeta subunit. At concentrations 1-5 nm or greater, insulin dose-dependently enhanced the tyrosine phosphorylation of IGF-IRbeta, and this was inhibited by IGF-IR neutralizing antibody. In addition, immunoprecipitation of IRbeta pulled down the IGF-IRbeta, and the IRbeta immunocytochemically colocalized with IGF-IRbeta, suggesting that ECs have insulin/IGF-I hybrid receptors. We conclude that: 1) insulin at physiological concentrations selectively activates IR signaling in bAECs; 2) bAECs express IGF-IR and insulin/IGF-I hybrid receptors in addition to IR; 3) high concentrations of insulin (>or=1-5 nM) activate IGF-IR and hybrid receptors as well as IR; and 4) this crossover activation can confound interpretation of studies of insulin action in ECs when high insulin concentrations are used.
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PMID:Insulin at physiological concentrations selectively activates insulin but not insulin-like growth factor I (IGF-I) or insulin/IGF-I hybrid receptors in endothelial cells. 1609 60

Deprivation of estrogen causes breast tumors in women to adapt and develop enhanced sensitivity to this steroid. Accordingly, women relapsing after treatment with oophorectomy, which substantially lowers estradiol for a prolonged period, respond secondarily to aromatase inhibitors with tumor regression. We have utilized in vitro and in vivo model systems to examine the biologic processes whereby long-term estradiol deprivation (LTED) causes cells to adapt and develop hypersensitivity to estradiol. Several mechanisms are associated with this response, including up-regulation of estrogen receptor-alpha (ERalpha) and the MAP kinase, phosphoinositol 3 kinase (PI3-K) and mammalian target of rapamycin (mTOR) growth factor pathways. ERalpha is four- to tenfold up-regulated and co-opts a classical growth factor pathway using Shc, Grb-2 and Sos. This induces rapid non-genomic effects which are enhanced in LTED cells. The molecules involved in the non-genomic signaling process have been identified. Estradiol binds to cell membrane-associated ERalpha, which physically associates with the adaptor protein Shc, and induces its phosphorylation. In turn, Shc binds Grb-2 and Sos, which result in the rapid activation of MAP kinase. These non-genomic effects of estradiol produce biologic effects as evidenced by Elk-1 activation and by morphologic changes in cell membranes. Additional effects include activation of the PI3-K and mTOR pathways through estradiol-induced binding of ERalpha to the IGF-I and epidermal growth factor receptors. A major question is how ERalpha locates in the plasma membrane since it does not contain an inherent membrane localization signal. We have provided evidence that the IGF-I receptor serves as an anchor for ERalpha in the plasma membrane. Estradiol causes phosphorylation of the adaptor protein, Shc and the IGF-I receptor itself. Shc, after binding to ERalpha, serves as the 'bus' which carries ERalpha to Shc-binding sites on the activated IGF-I receptors. Use of small inhibitor (si) RNA methodology to knockdown Shc allows the conclusion that Shc is needed for ERalpha to localize in the plasma membrane. In order to abrogate growth factor-induced hypersensitivity, we have utilized a drug, farnesylthiosalicylic acid, which blocks the binding of GTP-Ras to its membrane acceptor protein, galectin 1, and reduces the activation of MAP kinase. We have also shown that this drug is a potent inhibitor of mTOR as an additional mechanism of inhibition of cell proliferation. The concept of 'adaptive hypersensitivity' and the mechanisms responsible for this phenomenon have important clinical implications. The efficacy of aromatase inhibitors in patients relapsing on tamoxifen could be explained by this mechanism and inhibitors of growth factor pathways should reverse the hypersensitivity phenomenon and result in prolongation of the efficacy of hormonal therapy for breast cancer.
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PMID:Long-term estradiol deprivation in breast cancer cells up-regulates growth factor signaling and enhances estrogen sensitivity. 1611

Our understanding of the IGF-I system has increased dramatically in recent yr due in part to the advances in molecular and cellular biology. Not only can we now measure circulating levels of the members of this axis in order to address the possibly pathophysiological changes, but genetic alterations can now be identified as the underlying cause of specific clinical situations. In normal children, circulating levels of IGF-I and the IGF binding proteins (IGFBPs) change throughout development and in some cases are gender dependent. Children and adolescents with a variety of illnesses and metabolic disorders have altered circulating IGF-I and IGFBP levels. Hence, in children or adolescents with exogenous obesity, anorexia nervosa, coeliac disease, leukaemia and other types of cancer, as well as in cases of GH deficiency, this axis can be altered. These data may help us to understand the physiology and pathophysiology of this system, but the clinical or diagnostic utility of these measurements is still largely debated. Indeed, in most of the above mentioned illnesses, circulating IGF and IGFBP levels overlap with normal values. Furthermore, these measurements do not provide data concerning levels of these factors at target tissues or of local synthesis and autocrine-paracrine effects. However, measurements of IGF-I and its binding proteins, as well as GH and its binding proteins, can help us to focus our analysis of patients suspected to have genetic abnormalities on the GH receptor, IGF-I, its receptor, IGFALS, or intracellular signalling proteins such as STAT5b or ERK. Possibly, the most clear clinical utility of circulating IGF-I measurements in children is in cases of GH deficiency or insensitivity or under GH treatment. However, the fact there are cases of children with non-detectable levels of circulating IGF-I that yet normal height and growth velocity, or with non-detectable levels of GH yet normal growth and IGF-I levels, raises many questions. Furthermore, circulating IGF-I levels may be within the normal control levels and the child may have a pathological growth pattern. Hence, just how useful are these measurements? Another clinically important question pertains to GH treatment in patients, such as in the Turner Syndrome, where supraphysiological levels of serum IGF-I are reached in order to induce growth. The interpretation and clinical utility of measurements of circulating IGF-I and its BPs are currently being widely discussed. As our knowledge of this system increases, with the identification of new members of this family and its intracellular mechanisms of action, as well as new genetic alterations in patients, the interpretation of laboratory results will also improve and help to better our diagnostic capability.
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PMID:The IGF system in childhood: physiology and clinical implications. 1611 74

Paracrine cell signaling is believed to be important for ovarian follicle development, and a role for some members of the fibroblast growth factor (FGF) family has been suggested. In the present study, we tested the hypothesis that FGF-8 and its cognate receptors (FGFR3c and FGFR4) are expressed in bovine antral follicles. RT-PCR was used to analyze bovine Fgf8, Fgfr3c and Fgfr4 mRNA levels in oocytes, and granulosa and theca cells. Fgf8 expression was detected in oocytes and in granulosa and theca cells; this expression pattern differs from that reported in rodents. Granulosa and theca cells, but not oocytes, expressed Fgfr3c, and expression in granulosa cells increased significantly with follicle estradiol content, a major indicator of follicle health. Fgfr4 expression was restricted to theca cells in the follicle, and decreased significantly with increasing follicle size. To investigate the potential regulation of Fgfr3c expression in the bovine granulosa, cells were cultured in serum-free medium with FSH or IGF-I; gene expression was upregulated by FSH but not by IGF-I. The FSH-responsive and developmentally regulated patterns of Fgfr3c mRNA expression suggest that this receptor is a potential mediator of paracrine signaling to granulosa cells during antral follicle growth in cattle.
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PMID:Expression of fibroblast growth factor-8 and regulation of cognate receptors, fibroblast growth factor receptor-3c and -4, in bovine antral follicles. 1612 41

Growth factors are known to play diverse roles in steroidogenesis, a process regulated by the mitochondrial steroidogenic acute regulatory (StAR) protein. The mechanism of action of one such growth factor, IGF-I, was investigated in mouse Leydig tumor (mLTC-1) cells to determine its potential role in the regulation of StAR expression. mLTC-1 cells treated with IGF-I demonstrated temporal and concentration-dependent increases in StAR expression and steroid synthesis. However, IGF-I had no effect on cytochrome P450 side-chain cleavage or 3beta-hydroxysteroid dehydrogenase protein levels. IGF-I was capable of augmenting N,O'-dibutyrl-cAMP-stimulated steroidogenic responsiveness in these cells. The steroidogenic potential of IGF-I was also confirmed in primary cultures of isolated mouse Leydig cells. IGF-I increased phosphorylation of ERK1/2, an event inhibited by the MAPK/ERK inhibitors, PD98059 and U0126. Interestingly, inhibition of ERK activity enhanced IGF-I-mediated StAR protein expression, but phosphorylation of StAR was undetectable, an observation in contrast to that seen with N,O'-dibutyrl-cAMP signaling. Further studies demonstrated that these events were tightly correlated with the expression of dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene 1 and scavenger receptor class B type 1. Whereas both protein kinase A and protein kinase C signaling were involved in the IGF-I-mediated steroidogenic response, the majority of the effects of IGF-I were found to be mediated by the protein kinase C pathway. Transcriptional activation of the StAR gene by IGF-I was influenced by several transcription factors, its up-regulation being dependent on phosphorylation of the cAMP response element-binding protein (CREB) and the activator protein 1 family member, c-Jun. Conversely, StAR gene transcription was markedly inhibited by expression of nonphosphorylatable CREB (Ser(133)Ala), dominant negative A-CREB, and dominant negative c-Jun (TAM-67) mutants. Collectively, the present studies identify molecular events in IGF-I signaling that may influence testicular growth, development, and the Leydig cell steroidogenic machinery through autocrine/paracrine regulation.
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PMID:Molecular mechanisms of insulin-like growth factor-I mediated regulation of the steroidogenic acute regulatory protein in mouse leydig cells. 1616 97


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