Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Epidermal Growth Factor Receptor (EGFR) family, including EGFR, HER2, HER3, and HER4, is implicated in the development and progression of cancer, and is expressed in many human epithelial malignancies, including Non-Small Cell Lung Cancer (NSCLC). Several molecules were synthesized to inhibit the extracellular domain of EGFR, such as cetuximab (Erbitux), the extracellular domain of HER2, such as trastuzumab (Herceptin) or the EGFR tyrosine kinase domain, such as gefitinib (Iressa) and erlotinib (Tarceva). Gefitinib and erlotinib are orally active, selective EGFR tyrosine-kinase inhibitors (EGFR-TKI) that produce objective response rates in about 10% of advanced NSCLC. More recently, erlotinib produced a significant improvement in survival when compared to placebo in pretreated NSCLCs. Among clinical characteristics, although female gender, and adenocarcinoma histology, showed to be significantly associated to TKI sensitivity, never smoking history is probably the most relevant factor. Presence of specific EGFR gene mutations or EGFR gene amplification confer a particularly sensitive phenotype, and patients with activation of the anti-apoptotic protein Akt are more sensitive, when Akt activation is sustained by a EGFR dependent mechanism. Cetuximab is a human-murine chimeric anti-EGFR IgG monoclonal antibody that has demonstrated both in vitro and in vivo antitumor activity in tumor cell lines expressing EGFR. It has shown impressive activity when combined with radiation by increasing the antitumor effect of radiation therapy. Cetuximab has a synergistic effect with cisplatin and may play a role in reversing resistance to chemotherapy. Cetuximab demonstrated to be active in pretreated NSCLCs, and its activity as first-line therapy in combination with chemotherapy is currently under evaluation. Efforts should be made for the identification of biological mechanism underlying cetuximab sensitivity and emerging data suggest that the drugs is more active in patients with EGFR gene amplification. In NSCLC, trastuzumab produced disappointing results when combined with chemotherapy, but probably patients were not properly selected. Recent findings in gefitinib treated patients support HER2 analysis by fluorescence in situ hybridization as a complementary test for selection of patient candidate for EGFR targeted therapies. Combination of EGFR targeting agents with other biological drugs is under investigation.
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PMID:Epidermal growth factor receptor (EGFR) targeted therapies in non-small cell lung cancer (NSCLC). 1839 76

Intracellular Ca2+ overload induced by hypoxia-reoxygenation alters Ca2+ homeostasis, which plays an important role in myocardial cell injury. Even though propofol is known as a radical scavenger with Ca2+ channel blocking properties, little is known about cardioprotective effect associated with Ca2+ homeostasis in cardiomyocytes. In the present study, we showed that propofol protects cardiomyocytes against hypoxia-reoxygenation injury. In propofol-treated cardiomyocytes, we observed a decrease in the expression of pro-apoptotic protein Bax, cytochrome c, caspase-3 activation and intracellular Ca2+ content. We also found that propofol treatment enhanced expression of anti-apoptotic protein Bcl-2 and activation of ERK concerned with survival. Propofol attenuated alterations of genes involving Ca2+-regulatory mechanism and significantly modulated abnormal changes of SERCA2a genes in hypoxia-reoxygenated neonatal cardiomyocytes. These results suggest that propofol modulates the expression of genes involved in Ca2+ homeostasis, thereby producing cardioprotective effects through a reduction in apoptotic cell death.
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PMID:Effect of propofol on calcium homeostasis in hypoxia-reoxygenated neonatal rat cardiomyocytes. 1867 30

A major issue in the treatment of leukemia is resistance to chemotherapeutic drugs. The most common mechanism encountered in the laboratory is the increased efflux of hydrophobic cytotoxic drugs that is mediated by a family of energy-dependent transporters. Besides, resistance to apoptosis can also cause failure in the treatment of leukemia. Recently, we have introduced 4-(4-bromophenyl)-2,3-dihydro-N,3-bis(3,4,5-trimethoxyphenyl)-2-oxoidmidazole-1-carboxamide (MZ3) as a novel synthesized combretastatin A-4 analogue which is a potent and specific compound against leukemia cells both in vitro and in vivo. Aim of this study was to evaluate the effect of MZ3 on multidrug-resistant (MDR) cancer cells of leukemia, and explore the antimultidrug-resistant mechanisms. Here, we observed that the MDR leukemia cell models investigated, overexpressing MDR1 (P-gp), were hypersensitive against MZ3. Parental K562, HL60 cells and MDR1-overexpressing K562R, HL60R cells were employed in this study. MZ3 hypersensitivity was confirmed to be based on great apoptosis induction and cell cycle arrest at unaltered intracellular drug accumulation. Cell proliferation assay demonstrated that, compared with HL60 and K562 cells, HL60R and K562R cells exhibited 1.3-fold and 2.4-fold resistance to MZ3, showing 26.9-fold and 92.2-fold resistance to daunorubicin (DNR) respectively. Moreover, real-time RT-PCR result showed that MZ3 impacted the transcription of MDR1 gene and western blotting results indicated that MZ3 can activate apoptosis on MDR cells by downregulating the anti-apoptotic protein XIAP levels and inducing the decrease in the phosphorylation state of ERK. Summarizing, our data demonstrate that MZ3 can inhibit the MDR function of leukemia cells, and it exerts the effect through altering the transcription of MDR1 genes and downregulating the anti-apopotic protein levels. MZ3 may be a potential candidate for further research and development in anti-MDR territory.
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PMID:Antimultidrug-resistant effect and mechanism of a novel CA-4 analogue MZ3 on leukemia cells. 1871 89

Tumor necrosis factor-alpha (TNFalpha) stimulation of hepatocytes induces either cell survival or apoptosis, which seems to be regulated by the ubiquitin-proteasome system. Here we investigated the role of TNFalpha-induced down-modulation of the de-ubiquitinating enzyme USP2 for hepatocyte survival. Inhibition of hepatocyte apoptosis by pre-treatment with TNFalpha (TNFalpha tolerance) was analyzed in the mouse model of galactosamine/TNFalpha-induced liver injury and in actinomycin D/TNFalpha-treated primary mouse hepatocytes. The role of USP2 for TNFalpha-induced hepatocyte survival was studied using small interference RNA or an expression clone. Injection of mice or preincubation of hepatocytes with TNFalpha caused a rapid down-regulation of hepatic USP2-41kD, the predominant USP2 isoform in the liver. In vitro an artificial knockdown of USP2 inhibited actinomycin D/TNFalpha-induced hepatocyte apoptosis, which was associated with elevated levels of the anti-apoptotic protein c-Flip(L/S) and a concomitant decrease of cellular levels of the ubiquitinligase Itch, a negative regulator of c-Flip. USP2-41kD overexpression abrogated TNFalpha tolerance in vitro, prevented accumulation of c-Flip(L/S) and resulted in elevated levels of Itch. Accordingly, c-Flip(L/S) protein levels were elevated in livers of TNFalpha-tolerant mice, which correlated to a switch from JNK and ERK to p38 signaling after galactosamine/TNF re-challenge. Our results indicate that TNFalpha-induced USP2 down-regulation is an effective cytoprotective mechanism in hepatocytes. Hence, USP2 could be a novel pharmacological target, and specific USP2 inhibitors might be potential candidates for the treatment of inflammation-related apoptotic liver damage.
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PMID:Down-regulation of the de-ubiquitinating enzyme ubiquitin-specific protease 2 contributes to tumor necrosis factor-alpha-induced hepatocyte survival. 1900 62

The protein kinase Syk is a key mediator of proximal B-cell receptor (BCR) signaling. Following antigen stimulation, Syk is recruited to the BCR and becomes activated by phosphorylation at Y352. Recently, Syk was found to be constitutively phosphorylated in several common B-cell lymphoma subtypes, indicating a role for antigen-independent Syk activation in the pathogenesis of these diseases. We now report that Syk is constitutively phosphorylated on the activating Y352 residue in chronic lymphocytic leukemia (CLL) B cells. To examine the effects of constitutive Syk activity on intracellular signaling and leukemic cell survival, we performed in vitro studies with the Syk inhibitor R406. Treatment with R406 induced leukemic cell apoptosis in the majority of investigated cases and affected the basal activity or expression of several pro-survival molecules regulated by Syk, including the Akt and extracellular signal-regulated (ERK) kinases, and the anti-apoptotic protein Mcl-1. In addition, R406 prevented the increase in leukemic cell viability induced by sustained BCR engagement and inhibited BCR-induced Akt activation and Mcl-1 upregulation. Collectively, these data identify Syk as a potential target for CLL treatment and suggest that inhibition of this kinase could provide a double therapeutic benefit by disrupting both antigen-dependent and antigen-independent signaling pathways that regulate leukemic cell survival.
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PMID:Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B cells. 1909 49

Elevated expression of p130(Cas)/BCAR1 (breast cancer anti estrogen resistance 1) in human breast tumors is a marker of poor prognosis and poor overall survival. Specifically, p130(Cas) signaling has been associated with antiestrogen resistance, for which the mechanism is currently unknown. TAM-R cells, which were established by long-term exposure of estrogen (E(2))-dependent MCF-7 cells to tamoxifen, displayed elevated levels of total and activated p130(Cas). Here we have investigated the effects of p130(Cas) inhibition on growth factor signaling in tamoxifen resistance. To inhibit p130(Cas), a phosphorylated substrate domain of p130(Cas), that acts as a dominant-negative (DN) p130(Cas) molecule by blocking signal transduction downstream of the p130(Cas) substrate domain, as well as knockdown by siRNA was employed. Interference with p130(Cas) signaling/expression induced morphological changes, which were consistent with a more epithelial-like phenotype. The phenotypic reversion was accompanied by reduced migration, attenuation of the ERK and phosphatidylinositol 3-kinase/Akt pathways, and induction of apoptosis. Apoptosis was accompanied by downregulation of the expression of the anti-apoptotic protein Bcl-2. Importantly, these changes re-sensitized TAM-R cells to tamoxifen treatment by inducing cell death. Therefore, our findings suggest that targeting the product of the BCAR1 gene by a peptide which mimics the phosphorylated substrate domain may provide a new molecular avenue for treatment of antiestrogen resistant breast cancers.
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PMID:Expression of a phosphorylated p130(Cas) substrate domain attenuates the phosphatidylinositol 3-kinase/Akt survival pathway in tamoxifen resistant breast cancer cells. 1933 Jul 98

Cardiac apoptosis has been considered an important contributing factor to heart failure. Several subcellular mechanisms, including increased protein phosphatase 1 activity, have been suggested to induce apoptosis. Protein phosphatase 1 is regulated by an endogenous inhibitor-1 (I-1) that is activated upon phosphorylation at threonine 35 via protein kinase A. Here, we tested whether cardiac-specific overexpression of a constitutively active (T35D, AA 1-65) inhibitor-1 (I-1c), could also affect cardiac apoptosis and heart failure progression induced by prolonged beta-adrenergic stimulation. We found that either acute or chronic expression of I-1c reduced isoproterenol (ISO)-induced apoptosis assessed by nuclear condensation, TUNEL staining and DNA fragmentation. The beneficial effects of I-1c were associated with increased expression of the anti-apoptotic protein Bcl-2, decreased expression of the pro-apoptotic protein Bax and reduced levels of active caspases as well as increased activation of ERK. These findings suggest that mitochondrial signaling and ERK activation may be involved in the I-1c cardioprotective effects against apoptosis induced by prolonged beta-adrenergic stimulation.
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PMID:Expression of active protein phosphatase 1 inhibitor-1 attenuates chronic beta-agonist-induced cardiac apoptosis. 2052 8

Studies have demonstrated neuroprotective effects of either TNF-alpha or HSP-70 in ischemia/reperfusion injury following exercise. However, the protective mechanisms involving combined effect of the two proteins, particularly in neuronal apoptosis, remain unclear. This study aims to elucidate the beneficial role of TNF-alpha and HSP-70 in the regulation of apoptotic proteins and ERK signaling in hypoxic injury. Cortical neurons from 20 Sprague-Dawley rat embryos were isolated and cultured in five groups with or without pretreatment with recombinant TNF-alpha, HSP-70 protein or both prior to hypoxic conditions: (1) control; (2) control/hypoxia; (3) TNF-alpha/hypoxia; (4) HSP-70/hypoxia and (5) TNF-alpha/HSP-70/hypoxia. Western blotting was used to detect pro- and anti-apoptotic proteins, including Bax, AIF, Bcl-xL, Bcl-2, and pERK1/2 protein. TNF-alpha and HSP-70 significantly (p<0.05) reduced the levels of pro-apoptotic proteins, Bax and AIF. Also, pretreatment of hypoxic brain tissue with TNF-alpha and HSP-70 significantly (p<0.05) enhanced the levels of anti-apoptotic protein, Bcl-xL. TNF-alpha and HSP-70 together increased Bcl-2 levels by 70%. Hypoxia caused a significant (p<0.05) increase in ERK1/2 phosphorylation levels by 224%. The most effective inhibition of ERK levels was obtained by the combined administration of TNF-alpha and HSP-70. This study suggested that TNF-alpha and HSP-70 together enhance the decrease in pro-apoptotic protein levels and the increase in anti-apoptotic protein levels in the event of neuronal hypoxia through ERK1/2 signal transduction.
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PMID:Combined effect of tumor necrosis factor (TNF)-alpha and heat shock protein (HSP)-70 in reducing apoptotic injury in hypoxia: a cell culture study. 2069 Dec 48

Carbohydrate structures with a 3'-sulfo betaGal linkage, such as 3'-sulfo-Le(x), can be synthesized by Gal:3-O-sulfotransferase-2 (Gal3ST-2) catalysis, but little is known about their roles in many biological processes. To investigate the role of Gal3ST-2 and its product 3'-sulfo-Le(x), we depleted Gal3ST-2 via siRNA and added exogenous Lewis-x trisaccharide 3'-sulfate sodium salt in human SMMC7721 hepatoma cells. After siRNA transfection, a striking morphological change in SMMC7721 hepatoma cells from polygon to shuttle shape and a significant decrease in the level of adhesion to sL-selectin, HUVEC, fibronectin, vitronectin, and fibrinogen were observed. The expression of integrin subunit alphaV was markedly downregulated, and 3'-sulfated subunit alphaV almost disappeared in the transfectants. The level of cell surface integrin alphaVbeta3 was reduced simultaneously, although total subunit beta3 underwent almost no change. After treatment with exogenous Lewis-x 3'-sulfate, cellular integrin subunit alphaV was upregulated and the level of cell surface integrin alphaVbeta3 was elevated. Interestingly, knockdown of Gal3ST-2 expression effectively inhibited cell proliferation, and the result was significantly correlated with the decrease in the levels of ILK, phosphorylated AKT, and ERK. On the other hand, treatment with Lewis-x trisaccharide 3'-sulfate sodium salt greatly upregulated the phosphorylation of AKT and ERK. Our results also indicated that downregulation of Gal3ST-2 via siRNA transfection was associated with the decrease in the level of expression of anti-apoptotic protein, Bcl-2, with a consequent decrease in the ratios for Bcl-2 to Bax. By exposure to Lewis-x trisaccharide 3'-sulfate sodium salt, the apoptotic response of cells was inhibited. Therefore, Gal3ST-2 and its product, 3'-sulfo-Le(x), were involved in regulation of integrin subunit alphaV and might be associated with cancer cell regulation.
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PMID:3'-Sulfo-Le(x) is important for regulation of integrin subunit alphaV. 2069 81

The anti-apoptotic protein BCL-x(L) and the cell cycle inhibitor p21(CIP1/WAF1) were previously implicated in head and neck cancer. Several reports point to a role of the epidermal growth factor receptor (EGFR, ErbB-1, HER1) in regulating their expression. In the present study, we investigated the influence of EGFR on these tumor-associated factors. HNSCC cell lines were incubated with EGF or with the EGFR-specific kinase inhibitor AG1478. Western blot analysis and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were deployed to measure BCL-x(L) and p21(CIP1/WAF1) protein and mRNA levels. A dose-dependent rise of BCL-x(L) as well as p21(CIP1/WAF1) protein was noted after incubation with EGF, whereas inhibition with AG1478 reduced basal expression levels. No influence on BCL-2 was seen. Interestingly, qRT-PCR revealed that p21(CIP1/WAF1) but not BCL-x(L) transcript levels were induced after EGF treatment. Taken together, it can be stated that p21(CIP1/WAF1) and BCL-x(L) but not BCL-2 levels are tightly regulated by EGFR in HNSCC cell lines. BCL-x(L) induction appears to be due to protein stabilization rather than transcriptional activation, which is the likely cause of p21(CIP1/WAF1) induction. The noted variability in EGF response of HNSCC cells could reflect frequently observed variations in clinical response rates after implementation of anti-EGFR therapies.
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PMID:EGF-dependent induction of BCL-xL and p21CIP1/WAF1 is highly variable in HNSCC cells--implications for EGFR-targeted therapies. 2111 9


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