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 type 1 insulin-like growth factor receptor (IGF1R) is often overexpressed by tumors and mediates growth and apoptosis protection. We previously showed that antisense reagents complementary to the IGF1R translation start site enhance radio- and chemosensitivity and impair Atm function. However these agents induce relatively modest IGF1R down-regulation and affect insulin receptor levels. To identify alternative sites for molecular targeting, we utilized scanning oligonucleotide arrays to probe the secondary structure of IGF1R mRNA. This strategy enabled selection of antisense oligonucleotides that generated high heteroduplex yield with IGF1R but not insulin receptor transcripts. Antisense oligonucleotides that hybridized strongly to IGF1R mRNA caused IGF1R down-regulation within intact tumor cells, whereas weakly hybridizing oligonucleotides were inactive. Furthermore, the ability of small interfering RNAs (siRNAs) to block IGF1R expression correlated with the accessibility of the target sequence within the transcript. Thus, siRNAs corresponding to weakly hybridizing oligonucleotides caused minor IGF1R down-regulation, whereas siRNAs homologous to accessible targets induced profound sequence-specific IGF1R gene silencing, blocked IGF signaling, and enhanced tumor cell radiosensitivity. This indicates that secondary structure in the target transcript has a major effect on siRNA efficacy. These findings have implications for siRNA design and suggest that IGF1R-targeting agents incorporating this mode of action have potential as anticancer therapy.
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PMID:The efficacy of small interfering RNAs targeted to the type 1 insulin-like growth factor receptor (IGF1R) is influenced by secondary structure in the IGF1R transcript. 1260 14

The role of growth hormone (GH) in embryonic growth is controversial, yet preimplantation embryos express GH, insulin-like growth factor I (IGF-I) and their receptors. In this study, addition of bovine GH doubled the proportion of two-cell embryos forming blastocysts and increased by about 25% the number of cells in those blastocysts with a concentration-response curve showing maximal activity at 1 pg bovine GH ml(-1), with decreasing activity at higher and lower concentrations. GH increased the number of cells in the trophectoderm by 25%, but did not affect the inner cell mass of blastocysts. Inhibition of cell proliferation by anti-GH antiserum indicated that GH is a potent autocrine or paracrine regulator of the number of trophectoderm cells in vivo. Type 1 IGF receptors (IGF1R) were localized to cytoplasmic vesicles and plasma membrane in the apical domains of uncompacted and compacted eight-cell embryos, but were predominantly apparent in cytoplasmic vesicles of the trophectoderm cells of the blastocyst, similar to GH receptors. Studies using alpha IR3 antiserum which blocks ligand activation of IGF1R, showed that IGF1R participate in the autocrine or paracrine regulation of the number of cells in the inner cell mass by an endogenous IGF-I-IGF1R pathway. However, alpha IR3 did not affect GH stimulation of the number of trophectoderm cells. Therefore, GH does not use secondary actions via embryonic IGF-I to modify the number of blastocyst cells. This result indicates that GH and IGF-I act independently. GH may selectively regulate the number of trophectoderm cells and thus implantation and placental growth. Embryonic GH may act in concert with IGF-I, which stimulates proliferation in the inner cell mass, to optimize blastocyst development.
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PMID:Growth hormone, insulin-like growth factor I and cell proliferation in the mouse blastocyst. 1261 96

Small interfering RNAs (siRNAs) are powerful RNA interference (RNAi) reagents for directed post- transcriptional gene silencing. Exogenous siRNA is frequently used in RNAi studies. However, due to profound differences in the activity of siRNAs targeted to different regions of a gene, several reagents may have to be screened for optimal activity. This approach is expensive due to the cost of chemical synthesis of RNAs. We report a technically simple, quick and cost-effective method for the production of siRNAs that makes use of in vitro transcription and deoxyribozyme digestion of the transcripts to produce the desired sequence and length. The method allows for several siRNAs to be produced in parallel at much reduced costs. The siRNAs produced with this method were tested in MDA-MB-231 human breast cancer cells for efficacy against the type 1 insulin-like growth factor receptor (IGF1R) mRNA and they caused dose-dependent inhibition of IGF1R expression comparable to that induced by chemically synthesised siRNAs of the same sequence. This method is also useful for producing long RNA fragments of defined length and sequence that may be difficult to synthesise chemically, and also for producing large quantities of RNAs for applications including structural studies and the study of interactions between RNA and other molecules, such as proteins, other nucleic acids and drugs.
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PMID:A simple and cost-effective method for producing small interfering RNAs with high efficacy. 1265 26

Receptor tyrosine kinases (RTKs) such as Tie-2, IGF1R, Her-2/Neu, EGFR, and VEGFR1-3 play crucial roles in the control of cell growth and differentiation. Inhibition of such RTKs has become a major focus of current anticancer drug development, and therefore the discovery of new classes of inhibitors for these signal-transducing proteins is of prime importance. We have recently proposed a novel concept for improving the hit-finding process by employing natural products as biologically validated starting points in structural space for compound library development. In this concept, natural products are regarded as evolutionary chosen ligands for protein domains which are structurally conserved yet genetically mobile. Here we report on the discovery of novel and highly selective VEGFR-2 and -3, Tie-2, and IGF1R inhibitors derived from the naturally occurring Her-2/Neu kinase inhibitor nakijiquinone C and developed on the basis of this concept. Based on the structure of the natural product, a small library (74 members) was synthesized and investigated for inhibition of kinases with highly similar ATP-binding domains. The library yielded inhibitors with IC(50)s in the low micromolar range with high frequency (7 out of 74). In particular, four inhibitors of Tie-2 were found, a kinase critically involved in the formation of new blood vessels from preexisting ones (angiogenesis) and believed to be a new promising target in antitumor therapy. These results support the "domain concept". To advance the development of improved inhibitors, extensive molecular modeling studies were undertaken, including the construction of new homology models for VEGFR-2 and Tie-2. These studies revealed residues in the kinase structure which are crucial to the development of tailor-made receptor tyrosine kinase inhibitors.
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PMID:Development of natural product-derived receptor tyrosine kinase inhibitors based on conservation of protein domain fold. 1282 33

Various immunotoxins have been developed for the treatment of cancer. The toxin is internalized by target cells through cell-surface receptors, and it is essential for these receptors to be expressed for the immunotoxin to have specific anti-tumor activity. Radiation therapy is one of the main treatment modalities for primary malignant brain tumors. The purpose of this study was to determine whether radiation influences the expression of cell-surface receptors. Cells of one human medulloblastoma (Daoy) and two glioblastoma (U373-MG and T98-G) cell lines were tested by exposing the cells to a single dose of 5 Gy gamma rays. Expression of transferrin receptors, type-1 insulin-like growth factor receptors (IGF1R), and interleukin 4 receptors (IL4R) was measured by flow cytometry analysis on unirradiated cells and on cells 3 to 120 h after irradiation. In Daoy cells, the absolute expression index of transferrin receptors increased during the 24 h after irradiation with the greatest change of 26% above control at 9 h. The absolute expression index of IGF1R increased 26.5% above control at 12 h. The absolute expression index of IL4R decreased 9 h after irradiation. In U373-MG cells the absolute expression index of transferrin receptors increased during the 24 h after irradiation, and the greatest increase was 45% above control at 9 h. The absolute expression index of IGF1R increased during the 12 h after irradiation with a maximum increase of 33% above control at 6 h. The absolute expression index of IL4R decreased with time after irradiation. In T98-G cells, the absolute expression index of both transferrin receptors and IL4R decreased after irradiation. The results suggest that the expression of growth factor receptors on brain tumor cells may be influenced by radiation. The effect of ionizing radiation on receptor expression should be considered when administration of targeted toxin is combined with radiation. Similar studies with other growth factor receptors used in targeted toxin therapy are recommended.
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PMID:Changes in expression of transferrin, insulin-like growth factor 1, and interleukin 4 receptors after irradiation of cells of primary malignant brain tumor cell lines. 1285 34

The development of the mammary gland requires the coordinated expression of hormones and growth factors. Likewise, some transformed breast cells continue to respond to these same extracellular signals. Thus, understanding the mechanisms that control normal development of tissues can lead to new therapeutic targets. The insulin-like growth factor (IGF) system plays an important role in the normal development and function of the mammary gland. Accumulating evidence suggests that the IGFs are also key regulators of the malignant phenotype. The IGFs stimulate proliferation, promote survival, and enhance metastatic potential of breast cancer cells. Although multiple receptors for the IGFs have been identified, the IGFs primarily exert their biologic effects through ligation of the type I IGF receptor tyrosine kinase (IGF1R). IGF binding to the IGF1R initiates an intracellular signaling cascade that leads to changes in gene expression and cell biology. This review will focus on the evidence that the IGF1R is a relevant treatment target in breast cancer.
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PMID:The type-1 insulin-like growth factor receptor tyrosine kinase and breast cancer: biology and therapeutic relevance. 1288 9

We examined the role of IGF signaling in the remyelination process by disrupting the gene encoding the type 1 IGF receptor (IGF1R) specifically in the mouse brain by Cre-mediated recombination and then exposing these mutants and normal siblings to cuprizone. This neurotoxicant induces a demyelinating lesion in the corpus callosum that is reversible on termination of the insult. Acute demyelination and oligodendrocyte depletion were the same in mutants and controls, but the mutants did not remyelinate adequately. We observed that oligodendrocyte progenitors did not accumulate, proliferate, or survive within the mutant mice, compared with wild type, indicating that signaling through the IGF1R plays a critical role in remyelination via effects on oligodendrocyte progenitors.
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PMID:Insulin-like growth factor (IGF) signaling through type 1 IGF receptor plays an important role in remyelination. 1293 Aug 11

Short stature is a major concern for patients and their parents, and represents a diagnostic challenge to the clinician. A correct diagnosis is of particular importance in view of the availability of effective, but costly, therapy in a small subset of cases. Many different genetic etiologies of short stature are known. Therefore, chromosome as well as molecular analysis are requisite diagnostic investigations in children with short stature. Particularly in the group of children with idiopathic short stature, possibilities of molecular analysis are often underestimated. Important options are UPD7 and the FGFR3, SHOX, GH1 and GHR genes. Furthermore, analysis of the IGF and IGF1R genes should be considered. We propose a flow chart for molecular analysis in short stature.
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PMID:Genetic analysis of short stature. 1453 Jun 2

The type 1 insulin-like growth factor receptor (IGF1R) is overexpressed by many tumors, and mediates growth, motility and protection from apoptosis. Inhibition of IGF1R expression or function has been shown to block tumor growth and metastasis, and enhance sensitivity to cytotoxic drugs and irradiation. Thus the IGF1R is a highly promising anti-cancer treatment target. This review describes approaches to target the IGF1R using antibodies, small molecule inhibitors of the IGF1R tyrosine kinase, and molecular agents such as antisense and small interfering RNAs. Problems for the clinical introduction of this approach may include toxicity due to normal tissue IGF1R expression and cross-reactivity with the insulin receptor. The next few years will see clinical trials of IGF1R targeting, which offers genuine potential to inhibit tumor growth and chemoresistance in patients with cancer.
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PMID:Targeting the type 1 insulin-like growth factor receptor as anti-cancer treatment. 1455

We have previously shown that LCC6 wild-type (WT) cells, a metastatic variant of MDA-MB-435 cancer cells originally derived from a breast cancer patient, exhibit enhanced motility in response to IGF-I compared with the parent MDA-MB-435 cells. To further understand the role of the type I insulin-like growth factor (IGF) receptor (IGF1R) in cancer metastasis we inhibited signaling via IGF1R using a C-terminal-truncated IGF1R. The truncated receptor retains the ligand binding domain but lacks the autophosphorylated tyrosine residues in the carboxyl terminus. Cells stably transfected with this truncated receptor (LCC6-DN cells) overexpressed the truncated IGF1R messenger RNA nearly 50-fold over endogenous receptor. The truncated receptor in the LCC6-DN cells behaved in a dominant negative manner to inhibit endogenous IGF1R activation by IGF-I. Compared with the LCC6-WT cells, LCC6-DN cells failed to phosphorylate the adaptor proteins insulin receptor substrate-1 and -2 in response to IGF-I and did not activate Akt after exposure to IGF-I. Unlike LCC6-WT cells, LCC6-DN cells did not show enhanced motility in response to IGF-I. To assay for metastasis, LCC6-WT and LCC6-DN cells were injected into the mammary fat pads of mice, and the primary xenograft tumors were removed after 21 days. Mice sacrificed 5 weeks later showed multiple lung metastases derived from LCC-WT xenografts, whereas mice harboring LCC6-DN xenografts showed no lung metastases. Our data show that IGF1R can regulate several aspects of the malignant phenotype. In these cells, metastasis but not proliferation requires IGF1R function.
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PMID:A dominant negative type I insulin-like growth factor receptor inhibits metastasis of human cancer cells. 1461 89


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