Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ras proteins function through the formation of specific complexes with Raf-1, B-raf, PI-3 kinase and RalGDS. These interactions all require Ras-GTP with an intact effector binding domain (Switch I region). We have examined the requirements of the Switch II region (amino acids 60-72) for the production of stable interactions between Ras and its downstream effectors. A point mutation at position 65 or 64 combined with additional mutations at either position 65 or 71 rendered nucleotide-free Ras protein unable to stably interact with Ras specific guanine nucleotide exchange factors. Ha-Ras containing point mutations at positions 65 and 71 possessed a twofold higher affinity for B-raf and consequently MEK1. The point mutation at 64, in combination with additional point mutations at either position 65 or 71, resulted in a protein which failed to interact with either PI-3 kinase or neurofibromin, though these Ras mutants effectively bound both Raf-1 and B-raf. An activated form of Ras, Q61L-Ras, associated with all effector proteins independent of the bound guanine nucleotide. Q61L-Ras-GDP was almost as effective as wild type Ras-GMPPNP in the in vitro activation of MEK1 and MAP kinase. Competitive studies with the catalytic domain if neurofibromin, NF1-GRD, demonstrated that its interaction with Ras-GMPPNP is mutually exclusive with both Raf-1 and B-raf. These data suggest that rasGAP and neurofibromin are unable to downregulate Ras-GTP complexed to Raf-1 or B-raf.
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PMID:Different structural requirements within the switch II region of the Ras protein for interactions with specific downstream targets. 763 Jun 28

Thyroid-associated ophthalmopathy (TAO), an autoimmune component of Graves' disease, is associated with profound connective tissue remodeling and fibrosis that appear to involve the selective activation of orbital fibroblasts. Accumulation of extracellular matrix molecules is a hallmark of this process. Here we report that orbital fibroblasts treated with IL-1beta express high levels of tissue inhibitor of metalloproteinase-1 (TIMP-1), an important modulator of matrix metalloproteinase activity. These high levels are associated with increased TIMP-1 activity. The induction is mediated at the pretranslational level and involves activating the TIMP-1 gene promoter. IL-1beta activates the ERK 1/2 pathway in these fibroblasts and interrupting this signaling either with PD98059, a chemical inhibitor of MEK, or by transfecting cells with a dominant negative ERK 1 plasmid results in the attenuation of TIMP-1 induction. Surprisingly, treatment with IL-4 or IFN-gamma could also block the IL-1beta induction by attenuating TIMP-1 gene promoter activity. These findings suggest that TIMP-1 expression in orbital fibroblasts following activation with IL-1beta could represent an important therapeutic target for modifying the proteolytic environment. This might alter the natural course of tissue remodeling in TAO.
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PMID:Induction by IL-1 beta of tissue inhibitor of metalloproteinase-1 in human orbital fibroblasts: modulation of gene promoter activity by IL-4 and IFN-gamma. 1572 22

TSH receptor antibody (TRAb) is clinically classified into thyroid stimulating antibody (TSAb) and thyroid-stimulation blocking antibody (TSBAb). Although the former is considered to cause Graves' disease (GD), its activity does not necessarily reflect hormone production and goiter size. Moreover, uptake of 99mTcO4(-), the best indicator for GD, is correlated with activity of TSH binding inhibitor immunoglobulin better than activity of TSAb. Because uptake of 99mTcO4(-) reflects thyroid volume, these observations suggest that there exist TRAb with thyrocyte growth stimulating activity (GSA) other than TSAb. In this study, we analyzed GSA of monoclonal TRAb established from patients with GD or idiopathic myxedema (IME). GSA was measured as the degree of FRTL-5 cell growth stimulated by each TRAb. The signaling pathways of the cell growth were pharmacologically analyzed. The cell growth stimulated by TSH was strongly suppressed by protein kinase A (PKA) inhibitor, but was not affected by extracellular signal regulated kinase kinase (MEK) inhibitor. Although TSAb from GD stimulated the cell growth, both inhibitors suppressed it. Surprisingly, the cell growth was also induced by TSBAb from GD and was only suppressed by MEK inhibitor. TSBAb from IME did not have GSA and attenuated the cell growth stimulated by TSH. We concluded that 1; in GD, not only TSAb but some TSBAb could stimulate thyrocyte growth. 2; TSBAb might be classified with respect to their effects on thyrocyte growth; i.e., thyrocyte growth stimulating antibody and thyrocyte growth-stimulation blocking antibody.
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PMID:Growth stimulating antibody, as another predisposing factor of Graves' disease (GD): analysis using monoclonal TSH receptor antibodies derived from patients with GD. 2251 Sep 47

Runx2/Cbfa1 is a member of the Runt-related transcription factor family and is an essential regulator of osteoblast/chondrocyte differentiation. Recently, aberrant expression of Runx2 and its oncogenic functions have been identified in the progression and metastasis of human cancers. In this study, we investigated the expression profile of Runx family genes in normal thyroid tissue, non-neoplastic but abnormal thyroid tissue, various types of thyroid tumors and representative human thyroid carcinoma cell lines. Using reverse transcriptase-PCR and western blotting, we found that Runx2 was consistently upregulated in papillary carcinomas (PCs) and thyroid carcinoma cell lines compared with normal thyroid tissue. With immunohistochemistry, we observed negative or focal immunoreactivity of Runx2 in the nuclei of normal thyroid follicular cells. None of the non-neoplastic thyroid tissues, including Graves' thyroid and adenomatous goiter, had diffuse positivity of Runx2. Expression of Runx2 in benign follicular adenomas varied from negative to diffusely positive. Meanwhile, all malignant thyroid tumors showed some Runx2 immunopositivity. It was diffuse and intense in 83% (19/23) of PCs, 71% (5/7) of follicular carcinomas (FCs) and 40% (4/10) of undifferentiated carcinomas (UCs). In thyroid carcinoma cell lines, the MEK inhibitor U0126 suppressed Runx2, suggesting an association of the MAPK/ERK pathway with Runx2 regulation. Effective silencing of Runx2 by short interfering RNA (siRNA) demonstrated downregulation of EMT-related molecules (SNAI2, SNAI3 and TWIST1), MMP2 and vasculogenic factors (VEGFA and VEGFC) in thyroid carcinoma cells. We also confirmed that Runx2 silencing suppresses thyroid carcinoma cell invasion in transwell assays. In conclusion, this study provides insight into the potential molecular mechanism of thyroid cancer invasion. Our data suggest that enhanced Runx2 is functionally linked to tumor invasion and metastasis of thyroid carcinoma by regulating EMT-related molecules, matrix metalloproteinases and angiogenic/lymphangiogenic factors.
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PMID:Transcription factor Runx2 is a regulator of epithelial-mesenchymal transition and invasion in thyroid carcinomas. 2264 Oct 97

Malignant peripheral nerve sheath tumor (MPNST) is a rare aggressive form of sarcoma often associated with the tumor syndrome neurofibromatosis type 1 (NF1). We investigated the effects of tumor necrosis factor-related apoptosis inducing ligand (TRAIL) on NF1 associated MPNST and determinants of TRAIL sensitivity. MPNST cell lines with complete neurofibromin deficiency were sensitive to apoptotic cell death induced by TRAIL whereas MPNST cells with retained neurofibromin expression or normal human Schwann cells were resistant. Increased sensitivity to TRAIL was associated with overexpression of death receptors, especially DR5. Re-expression of the GAP related domain of neurofibromin (NF1-GRD) suppressed DR5 expression and decreased sensitivity to TRAIL. We show that death receptor expression and TRAIL sensitivity critically depend on c-MYC and that c-MYC amounts are increased by MEK/ERK and PI3K/AKT signalling pathways which are suppressed by neurofibromin. Furthermore PI3K/AKT signalling strongly suppresses the MYC-antagonist MAD1 which significantly contributes to TRAIL sensitivity. Re-expression of the NF1-GRD decreased c-MYC and increased MAD1 amounts suggesting that neurofibromin influences TRAIL sensitivity at least in part by modulating the MYC/MAX/MAD network. The phytochemical curcumin further increased the sensitivity of neurofibromin deficient MPNST cells to TRAIL. This was presumably mediated by ROS, as it correlated with increased ROS production, was blocked by N-acetylcysteine and mimicked by exogenous ROS.
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PMID:Sensitivity of malignant peripheral nerve sheath tumor cells to TRAIL is augmented by loss of NF1 through modulation of MYC/MAD and is potentiated by curcumin through induction of ROS. 2343 33

Earlier reports showed that hyperplasia of sympathoadrenal cell precursors during embryogenesis in Nf1-deficient mice is independent of Nf1's role in down-modulating RAS-MAPK signaling. We demonstrate in zebrafish that nf1 loss leads to aberrant activation of RAS signaling in MYCN-induced neuroblastomas that arise in these precursors, and that the GTPase-activating protein (GAP)-related domain (GRD) is sufficient to suppress the acceleration of neuroblastoma in nf1-deficient fish, but not the hypertrophy of sympathoadrenal cells in nf1 mutant embryos. Thus, even though neuroblastoma is a classical "developmental tumor", NF1 relies on a very different mechanism to suppress malignant transformation than it does to modulate normal neural crest cell growth. We also show marked synergy in tumor cell killing between MEK inhibitors (trametinib) and retinoids (isotretinoin) in primary nf1a-/- zebrafish neuroblastomas. Thus, our model system has considerable translational potential for investigating new strategies to improve the treatment of very high-risk neuroblastomas with aberrant RAS-MAPK activation.
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PMID:Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain. 2713 Jul 33