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)

Silver-Russell syndrome (SRS) describes a heterogeneous malformation syndrome mainly characterized by intrauterine and postnatal growth retardation (IUGR/PNGR). Approximately 10% of SRS cases have been associated with maternal uniparental disomy (matUPD) 7. This suggests the involvement of at least one imprinted gene on chromosome 7 in the pathogenesis of SRS. Additionally, two familial and one single SRS patients have been published with an interstitial duplication in 7p11.2-p13, including the genes GRB10 and IGFBP1; IGFBP3 was investigated in only one case revealing duplication; conversely, double gene dosage of EGFR was excluded in all 3 patients. Two further cytogenetically abnormal cases, one with a paracentric inversion (7)(p14p12) and one with matUPD7/partial trisomy for 7p13-q11, confirmed that the proximal short arm of chromosome represents an interesting region possibly harboring (a) candidate gene(s) for SRS. Although previously published investigations on the genes GRB10, IGFBP1, IGFBP3, and EGFR report neither disease-relevant mutations nor abnormal imprinting patterns, the SRS cases with chromosomal duplications suggest that variation of gene copy number might be a further type of mutation. To obtain meaningful results on the frequency of duplications in proximal 7p, we screened 32 SRS patients using quantitative PCR assays for GRB10, IGFBP1, IGFBP3, and EGFR. The data were confirmed by dual-color fluorescence in situ hybridization (FISH) of spot check samples. Results obtained by both methods exclude duplications in all analyzed patients and indicate an overall percentage of duplication among SRS patients between 2.4% (GRB10) and 5% (IGFBP1). By testing and evaluating quantitative competitive PCR for various loci, we developed a practical approach for gene dosage analysis which can be easily established for routine purposes.
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PMID:Gene dosage analysis in Silver-Russell syndrome: use of quantitative competitive PCR and dual-color FISH to estimate the frequency of duplications in 7p11.2-p13. 1178 94

Apoptosis of the cellular components of complex atherosclerotic plaque may lead to plaque instability and rupture. In this study, five primary plaques and one recurrent fibrointimal lesion obtained from patients undergoing carotid endarterectomy for symptomatic carotid stenosis > or = 70% were analyzed by immunohistochemistry and cDNA microarray to identify gene expression patterns that may determine plaque susceptibility or resistance to apoptosis. Immunohistochemistry showed expression of active caspase 3, an effector of apoptosis, in macrophages and lymphocytes surrounding the lipid core, in smooth muscle cells in the fibrous cap, and media of primary plaques as well as in occasional smooth muscle cells in the recurrent lesion. Among the genes demonstrating increased expression in primary plaques were IGFR2, DR4, DAPK1, Bak, and ERK 1 and 2 and those showing decreased expression included the TNF receptors 1 and 2, akt1, and IGFBP3. When comparing the recurrent lesion to the normal tissue, the expression of 13 genes was decreased by 3-fold, including IGFBP2 and IGFBP3, and none were increased by more than 1.5-fold. The analysis of gene expression patterns in primary and recurrent stenotic lesions provides a powerful approach to identify the signaling pathways that alter cellular apoptotic patterns in such lesions.
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PMID:Differential gene expression in primary and recurrent carotid stenosis. 1261 63

To investigate changes in gene expression associated with ERBB2, expression profiling of immortalized human mammary luminal epithelial cells and variants expressing a moderate and high level of ERBB2 has been carried out using cDNA microarrays corresponding to approximately 6000 unique genes/ESTs. A total of 61 significantly up- or downregulated (2.0-fold) genes were identified and further validated by RT-PCR analysis as well as microarray comparisons with a spontaneously ERBB2- overexpressing breast cancer cell line and ERBB2-positive primary breast tumors. The expression and clinical relevance of proteins predicted to be associated with ERBB2 overexpression in breast cancers were analysed together with their clinical relevance by antibody screening using a tissue array. Differentially regulated genes include those involved in cell-matrix interactions including proline 4-hydroxylase (P4HA2), galectin 1 (LGALS1) and galectin 3 (LGALS3), fibronectin 1 (FN1) and p-cadherin (CDH3), and cell proliferation (CRIP1, IGFBP3) and transformation (S100P, S100A4). A number of genes associated with MYC signalling were also differentially expressed, including NDRG1, USF2 and the epithelial membrane proteins 1 and 3 (EMP1, EMP3). These data represent profiles of the transcriptional changes associated with ERBB2-related pathways in the breast, and identify novel and potentially useful targets for prognosis and therapy.
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PMID:cDNA microarray analysis of genes associated with ERBB2 (HER2/neu) overexpression in human mammary luminal epithelial cells. 1273 Jun 82

Inappropriate exposure of neonatal sheep to estrogen during critical developmental periods inhibits or retards endometrial gland morphogenesis and reduces uterine growth. Studies were conducted to identify mechanisms mediating estrogen disruption of neonatal ovine uterine development by analysis of candidate growth factor systems and using suppression subtraction hybridization (SSH). In study 1, sheep were exposed either to corn oil as a control or to estradiol valerate (EV) from birth to Postnatal Day (PND) 14, which ablated endometrial gland development. Estradiol valerate decreased uterine FGF7 (fibroblast growth factor 7) and MET (hepatocyte growth factor receptor) expression and increased INHBA (inhibin betaA). The SSH identified a number of genes responsive to EV, which included GSTM3 (glutathione S-transferase), IDH1 (cytosolic NADP-isocitrate dehydrogenase), PECI (peroxisomal D(3),D(2)-enoyl-coenzyme A isomerase), OAS1 (2',5'-oligoadenylate 40/46-kDa synthetase), IGFBP3 (insulin-like growth factor-binding protein-3), TEGT (testis-enhanced gene transcript), CXCL10 (interferon-gamma-inducible protein 10), and IGLV (immunoglobulin V). These mRNAs were expressed predominantly in the endometrial epithelia (GSTM3, IDH1, PEC1, OAS1, and TEGT), stroma (IGFBP3), or immune cells (CXCL10 and IGLV). In study 2, effects of estrogen exposure on uterine gene expression were determined during three different critical developmental periods (PNDs 0-14, 14- 28, and 42-56). Estrogen exposure decreased expression of the SSH-identified genes, particularly those from PNDs 0-14. These studies suggest that estrogen disruption of postnatal uterine development involves period-specific effects on expression of genes predominantly in the endometrial epithelium. The SSH-identified, estrogen-disrupted genes represent new candidate regulators of postnatal endometrial adenogenesis.
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PMID:Estrogen disruption of neonatal ovine uterine development: effects on gene expression assessed by suppression subtraction hybridization. 1597 82

The majority of ovarian cancer patients are treated with platinum-based chemotherapy, but the emergence of resistance to such chemotherapy severely limits its overall effectiveness. We have shown that development of resistance to this treatment can modify cell signaling responses in a model system wherein cisplatin treatment has altered cell responsiveness to ligands of the erbB receptor family. A cisplatin-resistant ovarian carcinoma cell line PE01CDDP was derived from the parent PE01 line by exposure to increasing concentrations of cisplatin, eventually obtaining a 20-fold level of resistance. Whereas PE01 cells were growth stimulated by the erbB receptor-activating ligands, such as transforming growth factor-alpha (TGFalpha), NRG1alpha, and NRG1beta, the PE01CDDP line was growth inhibited by TGFalpha and NRG1beta but unaffected by NRG1alpha. TGFalpha increased apoptosis in PE01CDDP cells but decreased apoptosis in PE01 cells. Differences in extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling were also found, which may be implicated in the altered cell response to ligands. Microarray analysis revealed 51 genes whose mRNA increased by at least 2-fold in PE01CDDP cells relative to PE01 (including FRA1, ETV4, MCM2, AXL, MT3, TRAP1, and FANCG), whereas 36 genes (including IGFBP3, TRAM1, and KRT4 and KRT19) decreased by a similar amount. Differential display reverse transcriptase-PCR identified altered mRNA expression for TCP1, SLP1, proliferating cell nuclear antigen, and ZXDA. Small interfering RNA inhibition of FRA1, TCP1, and MCM2 expression was associated with reduced growth and FRA1 inhibition with enhanced cisplatin sensitivity. Altered expression of these genes by cytotoxic exposure may provide survival advantages to cells including deregulation of signaling pathways, which may be critical in the development of drug resistance.
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PMID:Altered ErbB receptor signaling and gene expression in cisplatin-resistant ovarian cancer. 1606 61

Obesity is a risk factor for postmenopausal breast cancer and is associated with poor prognosis. Leptin, a cytokine synthesized in adipose tissue, has been implicated as a link between obesity and breast cancer. In the present study, the effects of leptin on cell proliferation and proteins associated with leptin signaling and/or breast cell growth were investigated in ER-positive, MCF-7, T47-D and MDA-MB-361, and ER-negative, MDA-MB-231 and SK-BR-3, breast cancer cell lines. MDA-MB-361 and SK-BR-3 also overexpress HER2/neu. For proliferation assays, 96-well plates were used and for protein determinations cells were synchronized in 6-well plates for 18-24 h in serum-free medium. Leptin was added at 0, 5, 10, 25, 50 and 100 ng/ml for 24 and 48 h. For Western blot analyses, protein extracts were probed for Ob-Rb, Ob-R, leptin, Jak2, PI3K, Stat3, p-Stat3, PCNA, cyclin D1, Cox-2, VEGF, Bcl-2, Bcl-xL, Bax, insulin, IGF-I, IGFBP3, IGF-IRalpha, aromatase, CYP1A1 and CYP1B1. Overall, except for MCF-7 cells, leptin stimulated proliferation in all lines. MCF-7 cells expressed higher levels of Ob-Rb, Jak2, PI3K, Stat3 and p-Stat3 in a dose-dependent manner to 50 ng/ml at 24 h; and IGF-IRalpha increased at 24 h. Cyclin D1 and Cox-2 levels increased with leptin treatment. Higher CYP1B1 expression was observed at both 24 and 48 h. In MDA-MB-231 cells, p-Stat3 and Bcl-xL were increased at 48 h; whereas PCNA and cyclin D1 expression increased in leptin-treated cells at 24 and 48 h. In T47-D cells, Jak2 and Stat3 were elevated at higher leptin concentrations at 24 and 48 h. However, p-Stat3 and PCNA demonstrated an increase only in 48-h leptin-treated cells. Furthermore, cyclin D1 exhibited higher expression at both 24 and 48 h, while Bcl-xL expression was lower with increasing concentrations of leptin at 48 h. In MDA-MB-361 cells, Ob-Rb and VEGF increased at 24 and 48 h; whereas PI3K, Stat3, PCNA and insulin levels increased in leptin-treated MDA-MB-361 cells after 48 h. Bcl-2 and IGF-IRalpha were decreased at 24 h and a dose-dependent increase at 48 h was noted. Higher expression of CYP1B1 was observed with leptin for 24 h. In SK-BR-3 cells, Ob-R increased at both 24 and 48 h. A similar trend was found for IGF-I and IGFBP3 expression. Higher levels of Jak2 and PI3K were observed after 24 h. Interestingly, there was a gradual increase of leptin expression at 24 h, but a gradual decrease at 48 h in relation to the dose of leptin. In contrast, PCNA and IGF-IRalpha showed a decline at 24 h and an increase at 48 h. Elevated levels of cyclin D1, VEGF and Bax were detected at 48 h in cells and increased Cox-2 expression was observed at 24 h. These data indicate that leptin may influence breast cancer development in relation to ER status as well as to the presence or absence of HER2. Continued study on leptin may be helpful for a better understanding of breast cancer development in obese women.
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PMID:Effects of leptin on human breast cancer cell lines in relationship to estrogen receptor and HER2 status. 1748 72

Calcitriol is a standard therapy for secondary hyperparathyroidism in chronic renal failure. We evaluated whether the effect of daily or intermittent calcitriol administration is more efficient in enhancing bone growth in renal failure with advanced secondary hyperparathyroidism in weanling 5/6 nephrectomized rats loaded with phosphorus to induce severe secondary hyperparathyroidism. The animals were treated daily or three times weekly with calcitriol for 4 weeks but the total weekly dose of calcitriol was the same. Although calcitriol increased the serum calcium, it did not lower parathyroid hormone (PTH) or improve tibia and body length. Animals with renal failure and advanced secondary hyperparathyroidism had decreased PTH/PTHrP, which was accompanied by an increase in the cyclin kinase inhibitor p57(Kip2). Calcitriol treatment upregulated the PTH/PTHrP receptor but also increased inhibitors of cell proliferation such as p21(Waf1/Cip1), IGFBP3, and FGFR3. Calcitriol also enhanced markers of chondrocyte differentiation, such as IGF1, Vitamin D receptor, FGF23, and bone morphogenetic protein-7. Receptor activator of nuclear factor-kappabeta ligand levels improved with calcitriol treatment but without changes in osteoprotegerin suggesting an enhancement of osteo/chondroclastogenesis and mineralization. Overall, both daily and intermittent calcitriol had similar effects on endochondral bone growth in phosphorus-loaded rats with renal failure.
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PMID:Bone growth during daily or intermittent calcitriol treatment during renal failure with advanced secondary hyperparathyroidism. 1771 61

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, accounting for an estimated 600,000 deaths annually. Aberrant methylation, consisting of DNA hypomethylation and/or promoter gene CpG hypermethylation, is implicated in the development of a variety of solid tumors, including HCC. We analyzed the global levels of DNA methylation as well as the methylation status of 105 putative tumor suppressor genes and found that the extent of genome-wide hypomethylation and CpG hypermethylation correlates with biological features and clinical outcome of HCC patients. We identified activation of Ras and downstream Ras effectors (ERK, AKT, and RAL) due to epigenetic silencing of inhibitors of the Ras pathway in all HCC. Further, selective inactivation of SPRY1 and -2, DAB2, and SOCS4 and -5 genes and inhibitors of angiogenesis (BNIP3, BNIP3L, IGFBP3, and EGLN2) was associated with poor prognosis. Importantly, several epigenetically silenced putative tumor suppressor genes found in HCC were also inactivated in the nontumorous liver. Our results assign both therapeutic and chemopreventive significance to methylation patterns in human HCC and open the possibility of using molecular targets, including those identified in this study, to effectively inhibit HCC development and progression.
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PMID:Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma. 1771 5

The actions of IGFs are regulated at various levels. One mechanism involves binding to IGF-binding protein-3 (IGFBP-3) for transport, thus governing bioavailability. IGFBP3 transcription is modulated by many hormones and agents that stimulate or inhibit growth. We have previously shown in pediatric and adult cohorts a correlation between IGFBP-3 serum levels and two single-nucleotide polymorphisms (SNPs) located within the minimal promoter (-202 A/C and -185 C/T). Functionality of these SNPs was further explored in hepatic adenocarcinoma-derived SK-HEP-1 cells using transient transfections of luciferase constructs driven by different haplotypes of the IGFBP3 promoter. Basal luciferase activity revealed a significant haplotype-dependent transcriptional activity (at nucleotides -202 and -185, AC > CC, P < 0.001; AC > CT, P < 0.001; AC > AT, P < 0.001). Insulin treatment produced a similar haplotype dependence of luciferase activity (AC > CC, P = 0.002; AC > CT, P < 0.001; AC > AT, P = 0.011). However, induction ratios (insulin/control) for CC and AT were significantly higher compared with AC and CT (CC > AC, P = 0.03; CC > CT, P = 0.03; AT > AC, P = 0.03; AT > CT, P = 0.04). Gel retardation assays were used to identify upstream stimulatory factor (USF-1 and USF-2) methylation-dependent binding to E-box motifs located between the SNPs. Mutation of the USF binding site resulted in a significant loss of insulin stimulation of luciferase activity in the transfection assay. Chromatin immunoprecipitation with anti-USF-1/-2 showed an enrichment of IGFBP3 promoter in insulin-treated cells compared with unstimulated cells. Bisulfite sequencing of genomic DNA revealed that CpG methylation in the region of USF binding was haplotype dependent. In summary, we report a methylation-dependent USF binding site influencing the basal and insulin-stimulated transcriptional activity of the IGFBP3 promoter.
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PMID:Identification of upstream stimulatory factor binding sites in the human IGFBP3 promoter and potential implication of adjacent single-nucleotide polymorphisms and responsiveness to insulin. 1782 60

The insulin-like growth factor 1 (IGF1) signaling pathway is implicated in the development of cancer. High levels of circulating IGF1 and certain genetic polymorphisms of IGF1 and IGFBP3 are associated with an increased risk of several common cancers. The IGF1 receptor (IGF1R) has been shown to be expressed in a wide range of tumors, and IGF1R signaling is crucial for tumor transformation and the survival of malignant cells. Several monoclonal antibodies and small-molecule inhibitors have been tested in preclinical studies and early-phase clinical studies. IGF1R signaling interferes with numerous growth factors and receptors such as VEGF and EGFR. In the experimental system, IGF1R signaling has been found to correlate with resistance to therapies based on the inhibition of EGFR and HER2. This Review highlights the most relevant studies in this exciting area of research, focusing in particular on the role of IGF1R in resistance to other receptor-targeted therapies for cancer.
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PMID:Mechanisms of disease: signaling of the insulin-like growth factor 1 receptor pathway--therapeutic perspectives in cancer. 1789 9


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