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)

Both the ERK and phosphatidylinositol 3'-kinase (PI3K) signaling pathways can protect cells from apoptosis following withdrawal of survival factors. We have previously shown that the ERK1/2 pathway acts independently of PI3K to block expression of the BH3-only protein, BimEL, and prevent serum withdrawal-induced cell death, although the precise mechanism by which ERK reduced BimEL levels was unclear. By comparing Bim mRNA and Bim protein, expression we now show that the rapid expression of BimEL following serum withdrawal cannot be accounted for simply by increases in mRNA following inhibition of PI3K. In cells maintained in serum BimEL is a phosphoprotein. We show that activation of the ERK1/2 pathway is both necessary and sufficient to promote BimEL phosphorylation and that this leads to a substantial increase in turnover of the BimEL protein. ERK1/2-dependent degradation of BimEL proceeds via the proteasome pathway because it is blocked by proteasome inhibitors and is defective at the restrictive temperature in cells with a temperature-sensitive mutation in the E1 component of the ubiquitin-conjugating system. Finally, co-transfection of BimEL and FLAG-ubiquitin causes the accumulation of polyubiquitinated forms of Bim, and this requires the ERK1/2 pathway. Our findings provide new insights into the regulation of Bim and the role of the ERK pathway in cell survival.
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PMID:Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, Bim. 1264 60

Cyclin-dependent kinase (CDK) inhibitor p27Kip1 binds to the cyclin E.CDK2 complex and plays a major role in controlling cell cycle and cell growth. Our group and others have reported that anti-HER2 monoclonal antibodies exert inhibitory effects on HER2-overexpressing breast cancers through G1 cell cycle arrest associated with induction of p27Kip1 and reduction of CDK2. The role of p27Kip1 in anti-HER2 antibody-induced cell cycle arrest and growth inhibition is, however, still uncertain. Here we have provided several lines of evidence supporting a critical role for p27Kip1 in the anti-HER2 antibody-induced G1 cell cycle arrest and tumor growth inhibition. Induction of p27Kip1 and G1 growth arrest by anti-HER2 antibody, murine 4D5, or humanized trastuzumab (Herceptin) are concentration-dependent, time-dependent, irreversible, and long-lasting. The magnitude of G1 cell cycle arrest induced by trastuzumab or 4D5 is well correlated with the level of p27Kip1 protein induced. Up-regulation of p27Kip1 and G1 growth arrest could no longer be removed with as little as 14 h of treatment with trastuzumab. Anti-HER2 antibody-induced p27Kip1 protein, G1 arrest, and growth inhibition persist at least 5 days after a single treatment. The magnitude of growth inhibition of breast cancer cells induced by anti-HER2 antibody closely parallels the level of p27Kip1 induced. Induced expression of exogenous p27Kip1 results in a p27Kip1 level-dependent G1 cell cycle arrest and growth inhibition similar to that obtained with anti-HER2 antibodies. Reducing p27Kip1 expression using p27Kip1 small interfering RNA blocks anti-HER2 antibody-induced p27Kip1 up-regulation and G1 arrest. Treatment with anti-HER2 antibody significantly increases the half-life of p27Kip1 protein. Inhibition of ubiquitin-proteasome pathway, but not inhibition of calpain and caspase activities, up-regulates p27Kip1 protein to a degree comparable with that obtained with anti-HER2 antibodies. We have further demonstrated that anti-HER2 antibody significantly decreases threonine phosphorylation of p27Kip1 protein at position 187 (Thr-187) and increases serine phosphorylation of p27Kip1 protein at position 10 (Ser-10). Expression of S10A and T187A mutant p27Kip1 protein increases the fraction of cells in G1 and reduces a further antibody-induced G1 arrest. Consequently, p27Kip1 plays an important role in the anti-HER2 antibody-induced G1 cell cycle arrest and tumor growth inhibition through post-translational regulation. Regulation of the phosphorylation of p27Kip1 protein is one of the post-translational mechanisms by which anti-HER2 antibody upregulates the protein.
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PMID:The role of cyclin-dependent kinase inhibitor p27Kip1 in anti-HER2 antibody-induced G1 cell cycle arrest and tumor growth inhibition. 1270 Feb 33

Global gene expression analysis using microarrays has been used to characterize the molecular profile of tumors. Gene expression variability at the mRNA level can be caused by a number of different events, including novel signaling, downstream activation of transcription enhancers or silencers, somatic mutation, and genetic amplification or deletion. Genomic amplifications are commonly observed in cancer and often include known oncogenes. The tyrosine kinase-type cell surface receptor, ERBB2, is an oncogene located on chromosome 17q21.1 that is amplified in 10-40% of breast tumors. We report for the first time that phenylethanolamine N-methyltransferase (PNMT), proteasome subunit, beta type 3 (PSMB3), ribosomal protein L19 (RPL19), and nuclear receptor subfamily 1, group D, member 1 (NR1D1) are coexpressed with ERBB2 in 34 breast cancer biopsies and also mapped within the same chromosomal location as the ERBB2 gene. Consistent with previous reports, we also observed that the steroidogenic acute regulatory protein-related gene, MLN64, and growth factor receptor bound protein 7 were coexpressed with ERBB2. Coexpression and colocalization of PNMT and MLN64 with ERBB2 suggested that the amplification of ERBB2 includes the chromosomal region harboring these genes. This hypothesis was validated in a subset of 12 biopsies. Gene amplification of ERBB2, PNMT, and MLN64 significantly correlated with increased mRNA gene expression (P < 0.05). These results suggest that gene expression profiling of breast biopsies may become a valuable method for adequately characterizing and choosing treatment modality for patients with breast cancer.
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PMID:Gene expression profiling detects gene amplification and differentiates tumor types in breast cancer. 1272 39

Ras promotes the accumulation of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1) (p21). Previous studies reported that acute Raf/MEK/ERK activation elevates p21 protein levels by increased transcription. However, we have found that p21 induction in Ras-transformed murine fibroblasts occurs principally by a post-translational mechanism. Chronic activation of the Raf/MEK/ERK pathway blocked proteasome-mediated p21 degradation, resulting in accumulation of p21 protein with an elevated half-life. The stabilization of p21 by Ras was accompanied by high levels of p21-associated cyclin D1 and, similarly to Ras, cyclin D1 was sufficient to inhibit the proteasome-mediated p21 degradation. Knock-down of cyclin D1 by RNA interference confirmed that Ras-induced p21 stabilization was dependent upon cyclin D1 expression. We show that p21 directly binds to the C8alpha subunit of the 20S proteasome complex and that by competing for binding, cyclin D1 inhibits p21 degradation by purified 20S complexes in vitro. Therefore, we propose that Ras stabilizes p21 by promoting the formation of p21-cyclin D1 complexes that prevent p21 association with, and subsequent degradation by, the 20S proteasome.
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PMID:Ras promotes p21(Waf1/Cip1) protein stability via a cyclin D1-imposed block in proteasome-mediated degradation. 1272 71

Previous work has shown that phorbol esters modulate chemotaxis. Here, we demonstrate that PKC activation via phorbol 12-myristate 13-acetate (PMA) treatment of MDA-MB-231 cells inhibits EGF-induced cell spreading, the initial event of motility and chemotaxis. Of five PKC isoforms (alpha,iota,lambda,delta,and epsilon) identified in this cell line, PMA treatment only induced PKCalpha translocation from the cytosol to the membrane, an event that correlated with the development of the rounded morphology. Cell recovery was linked to PKCalpha downregulation in part via the proteasome pathway since treatment with MG101 in the presence of PMA did not lead to PKCalpha degradation and cell recovery. Co-immunoprecipitation and immunolocalization demonstrated that EGF co-localized with PKCalpha and EGFR, however, PMA did not abrogate EGFR transactivation. This work suggests that PKCalpha is the primary target of PMA acting as a transient negative regulator of cell spreading and motility in MDA-MB-231 breast cancer cells.
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PMID:Protein kinase Calpha negatively regulates cell spreading and motility in MDA-MB-231 human breast cancer cells downstream of epidermal growth factor receptor. 1287 87

The mechanisms involved in the anti-angiogenic actions of the proteasome inhibitors are poorly understood. Here, we report that the gene expression of the VEGF receptor Flt-1 (vascular endothelial growth factor receptor 1) was down-regulated by the reversible proteasome inhibitor MG262 in explant cultures of the developing chicken pecten oculi, a vascular organ consisting of endothelial cells, pericytes, and macrophages. In addition, the inhibitor prevented the induction of Flt-1 by lipopolysaccharide (LPS) in macrophages and down-regulated the expression of Flt-1 after LPS induction. Flt-1 gene expression was also down regulated by MG262 in cultures of human microvascular endothelial cells. Interestingly, a transcript of Flt-1, coding for a soluble form of the receptor (sFlt-1) with anti-angiogenic properties, was not down-regulated in the same extent. Only a small decrease in the expression of VEGF and Ang-2 was detected in the pecten oculi upon inhibition of the proteasome, while no major changes were observed in the expression of other angiogenic molecules, such as KDR or Ang-1. Since recent experiments have demonstrated the importance of anti-Flt-1 therapy in the inhibition of tumor angiogenesis, retinal angiogenesis, arthritis, and atherosclerosis (Luttun et al. [2002]: Nat Med 8:831-840), our observation on down-regulation of Flt-1 in microvascular endothelial cells and macrophages by MG262 supports the postulated role of the proteasome inhibitors as potential candidates for therapeutic modulation of angiogenesis and inflammation.
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PMID:Down-regulation of Flt-1 gene expression by the proteasome inhibitor MG262. 1289 12

Genetic heterogeneity between individuals confounds the comparison of gene profiling of multiple myeloma (MM) cells versus normal plasma cells (PCs). To overcome this barrier, we compared the gene expression profile of CD138+ MM cells from a patient bone marrow (BM) sample with CD138+ PCs from a genetically identical twin BM sample using microarray profiling. Two hundred and ninety-six genes were up-regulated and 103 genes were down-regulated at least 2-fold in MM cells versus normal twin PCs. Highly expressed genes in MM cells included cell survival pathway genes such as mcl-1, dad-1, caspase 8, and FADD-like apoptosis regulator (FLIP); oncogenes/transcriptional factors such as Jun-D, Xbp-1, calmodulin, Calnexin, and FGFR-3; stress response and ubiquitin/proteasome pathway-related genes and various ribosomal genes reflecting increased metabolic and translational activity. Genes that were down-regulated in MM cells versus healthy twin PCs included RAD51, killer cell immunoglobulin-like receptor protein, and apoptotic protease activating factor. Microarray results were further confirmed by Western blot analyses, immunohistochemistry, fluorescent in situ hybridization (FISH), and functional assays of telomerase activity and bone marrow angiogenesis. This molecular profiling provides potential insights into mechanisms of malignant transformation in MM. For example, FGFR3, xbp-1, and both mcl-1 and dad-1 may mediate transformation, differentiation, and survival, respectively, and may have clinical implications. By identifying genes uniquely altered in MM cells compared with normal PCs in an identical genotypic background, the current study provides the framework to identify novel therapeutic targets.
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PMID:Identification of genes modulated in multiple myeloma using genetically identical twin samples. 1296 76

The Vesl-1S/Homer-1a protein is induced during long-term potentiation (LTP), and contains a motif that binds postsynaptic proteins. We have previously reported that synaptic accumulation of Vesl-1S/Homer-1a immunoreactivity (IR) at synapses on the contour of neuronal somata is promoted by stimulation of cells with phorbol esters, 90 mM KCl or proteasome inhibitors. In the present study, we investigated the intracellular mechanism that results in the synaptic accumulation of this protein at synapses. MEK inhibitors completely blocked the effects of phorbol esters and KCl on the accumulation of Vesl-1S/Homer-1a and partially blocked the effect of proteasome inhibitors. Conversely, brain-derived neurotrophic factor (BDNF) and NT3 promoted the accumulation of Vesl-1S/Homer-1a IR at synapses. The extent of this accumulation is correlated with the level of activation of extracellular signal-regulated kinases, ERK following treatment with BDNF. BDNF also caused an increase in the amount of Vesl-1S/Homer-1a protein, but this occurred after Vesl-1S/Homer-1a had accumulated at the synapses. In addition, inhibition of de novo protein synthesis did not affect the phorbol ester-mediated accumulation of Vesl-1S/Homer-1a IR at synapses. These results indicate that activation of the ERK cascade plays a crucial role in the synaptic accumulation of Vesl-1S/Homer-1a IR, and suggest that this accumulation occurs mainly by re-localization of Vesl-1S/Homer-1a protein, and not through an increase in the level of Vesl-1S/Homer-1a. Activity-dependent release of neurotrophins or depolarization may cause local activation of the ERK cascade to produce the synapse-specific localization of Vesl-1S/Homer-1a.
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PMID:Activation of ERK cascade promotes accumulation of Vesl-1S/Homer-1a immunoreactivity at synapses. 1455 52

Experimentally and clinically, stroke is followed by both acute and prolonged inflammatory responses characterized by the production of inflammatory cytokines and leukocyte infiltration into the brain. A debate on whether inflammation after stroke is neurotoxic or participates in brain repair remains unresolved. However, the need to pharmacologically control inflammatory amplification has been commonly acknowledged. The principal challenge of devising successful anti-inflammatory strategies for stroke is to understand molecular and temporal interplay of inflammatory and cell-death-inducing processes triggered by cerebral ischemia in both parenchymal and vascular brain cells. This article will review a number of experimental and clinically tested approaches to reduce brain inflammation and damage after stroke (e.g., anti-neutrophil, anti-ICAM-1, anti-cytokine strategies) and will suggest potential pathways where novel therapeutic targets may emerge, including transcriptional regulators of inflammatory gene expression (e.g., NF-kappaB, proteasome) and signaling pathways (e.g., ICE-cascade, MAPK/MKK/ERK cascade) linked to both inflammation and neuronal cell death. Finally, we will discuss applications of functional genomics technologies in the discovery of stroke diagnostics and therapies.
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PMID:Current and future therapeutic strategies to target inflammation in stroke. 1456 Nov 97

Cellular senescence is characterized by impaired cell proliferation. We have previously shown that, relative to the young counterpart, senescent WI-38 human fibroblasts display a decreased abundance of active phosphorylated ERK (p-ERK) in the nucleus. We have tested the hypothesis that this is due to elevated levels of nuclear MAP kinase phosphatase (MKP) activity in senescent cells. Our results indicate that the activity and abundance of MKP-2 is increased in senescent fibroblasts, compared to their young counterparts. Further analysis indicates that it is MKP-2 protein, but not MKP-2 mRNA level, that is increased in senescent cells. This increase is the result of the increased stability of MKP-2 protein against proteolytic degradation. The degradation of MKPs was impaired by proteasome inhibitors both in young and old WI-38 cells, indicating that proteasome activity is involved in the degradation of MKPs. Finally, our results indicate that proteasome activity, in general, is diminished in senescent fibroblasts. Taken together, these data indicate that the increased level and activity of MKP-2 in senescent WI-38 cells are the consequence of impaired proteosomal degradation, and this increase is likely to play a significant role in the decreased levels of p-ERK in the nucleus of senescent cells.
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PMID:Metabolic stabilization of MAP kinase phosphatase-2 in senescence of human fibroblasts. 1456 79


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