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

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of the current study was to evaluate the protein expression involved in the progression from dysplasia to invasive esophageal squamous cell carcinomas and to analyze the prognostic value of markers. Immunohistochemistry was performed for cell cycle regulators [p53, p21, p27, p16, cyclin D1, Rb], apoptosis-related proteins [Fas, Fas-L, FADD, TRAIL, DR4, DR5, caspase-8, caspase-3, bcl-2, Bax], tumor suppressor proteins [beta-catenin, E-cadherin, FHIT, Smad 4, VHL, PTEN, KAI-1], and oncoproteins [c-myc, COX-2, EGFR]. Caspase-3, TRAIL, Fas-L, Fas, Smad 4, VHL, E-cadherin, and EGFR revealed significant differences between dysplasia and their corresponding invasive cancer portion in 25 cases. In a total of 118 cases of invasive cancer, proteins with frequent (> or = 60% of the cases) alterations were p53 (overexpression in 64% of SCCs), p27 (loss in 91%), p16 (loss in 81%), and FHIT (loss in 75%). Early clinical stage and bcl-2 immunopositivity were related to the survival rate of patients. In conclusion, caspase-3, TRAIL, Fas-L, Fas, Smad 4, VHL, E-cadherin, and EGFR may be involved in the progression from dysplasia to invasive esophageal SCCs. Clinical stage and bcl-2 are independent prognostic factors throughout the multivariate analysis.
...
PMID:Differential protein expression between esophageal squamous cell carcinoma and dysplasia, and prognostic significance of protein markers. 1613 47

We sought to evaluate the biological function of the receptor tyrosine kinase EphB4 in bladder cancer. All of the nine bladder cancer cell lines examined express EphB4 and the receptor could be phosphorylated following stimulation with its cognate ligand, EphrinB2. Out of the 15 fresh bladder cancer specimens examined, 14 expressed EphB4 with a mean sevenfold higher level of expression compared to adjacent normal urothelium. EphB4 expression was regulated by several mechanisms: EPHB4 gene locus was amplified in 27% tumor specimens and 33% cell lines studied; inhibition of EGFR signaling downregulated EphB4 levels; and forced expression of wild-type p53 reduced EphB4 expression. EphB4 knockdown using specific siRNA and antisense oligodeoxynucleotides molecules led to a profound inhibition in cell viability associated with apoptosis via activation of caspase-8 pathway and downregulation of antiapoptotic factor, bcl-xl. Furthermore, EphB4 knockdown significantly inhibited tumor cell migration and invasion. EphB4 knockdown in an in vivo murine tumor xenograft model led to a nearly 80% reduction in tumor volume associated with reduced tumor proliferation, increased apoptosis and reduced tumor microvasculature. EphB4 is thus a potential candidate as a predictor of disease outcome in bladder cancer and as target for novel therapy.
...
PMID:EphB4 receptor tyrosine kinase is expressed in bladder cancer and provides signals for cell survival. 1620 42

Expression of isolated beta integrin cytoplasmic domains in cultured endothelial cells was reported to induce cell detachment and death. To test whether cell death was the cause or the consequence of cell detachment, we expressed isolated integrin beta1 cytoplasmic and transmembrane domains (CH1) in cultured human umbilical vein endothelial cells (HUVEC), and monitored detachment, viability, caspase activation and signaling. CH1 expression induced dose-dependent cell detachment. At 24 h over 90% of CH1-expressing HUVEC were detached but largely viable (>85%). No evidence of pro-caspase-8,-3, and PARP cleavage or suppression of phosphorylation of ERK, PKB and Ikappa-B was observed. The caspase inhibitor z-VAD did not prevent cell detachment. At 48 h, however, CH1-expressing cells were over 50% dead. As a comparison trypsin-mediated detachment resulted in a time-dependent cell death, paralleled by caspase-3 activation and suppression of ERK, PKB and Ikappa-B phosphoyrylation at 24 h or later after detachment. HUVEC stimulation with agents that strengthen integrin-mediated adhesion (i.e. PMA, the Src inhibitor PP2 and COMP-Ang1) did not prevent CH1-induced detachment. Expression of CH1 in rat carotid artery endothelial cells in vivo caused endothelial cell detachment and increased nuclear DNA fragmentation among detached cells. A construct lacking the integrin cytoplasmic domain (CH2) had no effect on adhesion and cell viability in vitro and in vivo. These results demonstrate that isolated beta1 cytoplasmic domain expression induces caspase-independent detachment of viable endothelial cells and that death is secondary to detachment (i.e. anoikis). They also reveal an essential role for integrins in the adhesion and survival of quiescent endothelial cells in vivo.
...
PMID:Expressed isolated integrin beta1 subunit cytodomain induces endothelial cell death secondary to detachment. 1636 50

Oridonin, an active component isolated from Rabdosia rubescences, has been reported to have antitumor effects. In this study, we compared the signal transduction pathways between TNFalpha-and oridonin-induced L929 cell death. Oridonin and TNFalpha initiated apoptotic morphologic changes, but DNA fragmentation was found in TNFalpha-treated L929 cells but not in oridonin-treated ones. The pan-caspase inhibitor (z-VAD-fmk), caspase-8 inhibitor (z-IETD-fmk) and caspase-3 inhibitor (z-DEVD-fmk) augmented oridonin-and TNFalpha-induced cell death. However, the caspase-9 inhibitor (z-LEHD-fmk) only increased oridonin-induced L929 cell death. Moreover, poly (ADPribose) polymerase (PARP) was cleaved in oridonin-treated L929 cells but not in the TNFalpha-treated groups, and the caspase-3 inhibitor (z-DEVD-fmk) failed to inhibit PARP cleavage. These results showed that only oridonin-induced L929 cell death required PARP degradation in a caspase-3 independent manner. In addition, oridonin increased the ratio of Bax/Bcl-2 protein expression, but TNFalpha did not. TNFalpha induced p38 and ERK activation, whereas oridonin triggered only ERK activation. We also investigated the effect of oridonin on intracellular TNFalpha expression, and found that oridonin augmented endogenous pro-TNFalpha expression and its upstream protein IkB phosphorylation. These results indicated that although oridonin promoted endogenous pro-TNFalpha expression, a great difference existed between the signal pathways through which TNFalpha-and oridonin-induced cell death.
...
PMID:A comparison of the signal pathways between the TNF alpha- and oridonin-induced murine L929 fibrosarcoma cell death. 1641 69

Erythropoietin (EPO), a pleiotropic cytokine involved in erythropoiesis, is tissue-protective in ischemic, traumatic, toxic and inflammatory injuries. In this study, we investigated the effect of EPO in experimental intracerebral hemorrhage (ICH). Two hours after inducing ICH via the stereotaxic infusion of collagenase, recombinant human EPO (500 or 5000 IU/kg, ICH + EPO group) or PBS (ICH + vehicle group) was administered intraperitoneally, then once daily afterwards for 1 or 3 days. ICH + EPO showed the better functional recovery in both rotarod and modified limb placing tests. The brain water content was decreased in ICH + EPO dose-dependently, as compared with ICH + vehicle. The effect of EPO on the brain water content was inhibited by N(omega)-Nitro-L-arginine methyl ester hydrochloride (L-NAME, 10 mg/kg). Mean hemorrhage volume was also decreased in ICH + EPO. EPO reduced the numbers of TUNEL +, myeloperoxidase + or OX-42 + cells in the perihematomal area. In addition, EPO reduced the mRNA level of TNF-alpha, Fas and Fas-L, as well as the activities of caspase-8, 9 and 3. EPO treatment showed up-regulations of endothelial nitric oxide synthase (eNOS) and p-eNOS, pAkt, pSTAT3 and pERK levels. These data suggests that EPO treatment in ICH induces better functional recovery with reducing perihematomal inflammation and apoptosis, coupled with activations of eNOS, STAT3 and ERK.
...
PMID:Erythropoietin reduces perihematomal inflammation and cell death with eNOS and STAT3 activations in experimental intracerebral hemorrhage. 1653 88

The pathway of interferon-gamma (IFN-gamma)-induced suppression in tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells (FLS) was investigated. rTRAIL triggered FLS apoptosis in a type II cell death manner, whereas IFN-gamma pretreatment significantly inhibited TRAIL-mediated apoptosis. As disruption of mitochondrial transmembrane potential (DeltaPsim), Leu-Glu-His-Asp ase (IETD ase) activity, and the appearance of hypodiploid DNA + cells were markedly suppressed in IFN-gamma-treated FLS in response to TRAIL, IFN-gamma-induced suppression was supposed to achieve at upstream of caspase-8. IFN-gamma rapidly phosphorylated signal transducers and activators of transcription 1 (STAT1), STAT3, and STAT6 as well as ERK, whereas enhanced neither phosphorylation of Akt nor nuclear translocation of nuclear factor kappaB (NF-kappaB) p65. Janus kinase (JAK)-induced phosphorylation of STAT1/3/6, which acts at translational regulation, seemed to be crucial because chemical inhibition of JAK as well as cycloheximide (CHX) abolished both the phosphorylation of STAT1/3/6 and the IFN-gamma-induced inhibitory effect. Although ERK was phosphorylated through IFN-gamma, chemical inhibition of ERK by PD98059 did not abolish the IFN-gamma-induced inhibitory effect. The authors tried to determine the responsible molecules; however, expression of TRAIL receptors; pro-caspase-3/-8/-9; Fas-associated death domain protein (FADD); tumor necrosis factor receptor 1-associated death domain protein (TRADD); silencer of death domain (SODD); FLICE inhibitory protein (FLIP); and Bcl-2, Bcl-xL, and Bax in FLS was not modulated by IFN-gamma. Although the authors have not yet clarified the precise mechanism, these data suggest that IFN-gamma/JAK/STAT pathway, which is supposed to be activated in inflammatory rheumatoid arthritis (RA) synovial tissues, contributes to form apoptosis resistance phenotype of the cells in situ, leading to a marked increase in cellularity of synovial cells.
...
PMID:Significant inhibition of TRAIL-mediated fibroblast-like synovial cell apoptosis by IFN-gamma through JAK/STAT pathway by translational regulation. 1658 46

The receptor tyrosine kinase EphB4 and its ligand EphrinB2 play critical roles in blood vessel maturation, and are frequently overexpressed in a wide variety of cancers. We studied the aberrant expression and biological role of EphB4 in head and neck squamous cell carcinoma (HNSCC). We tested the effect of EphB4-specific siRNA and antisense oligonucleotides (AS-ODN) on cell growth, migration and invasion, and the effect of EphB4 AS-ODN on tumor growth in vivo. All HNSCC tumor samples express EphB4 and levels of expression correlate directly with higher stage and lymph node metastasis. Six of 7 (86%) HNSCC cell lines express EphB4, which is induced either by EGFR activation or by EPHB4 gene amplification. EphrinB2 was expressed in 65% tumors and 5 of 7 (71%) cell lines. EphB4 provides survival advantage to tumor cells in that EphB4 siRNA and AS-ODN significantly inhibit tumor cell viability, induce apoptosis, activate caspase-8, and sensitize cells to TRAIL-induced cell death. Furthermore, EphB4-specific AS-ODN significantly inhibits the growth of HNSCC tumor xenografts in vivo. Expression of EphB4 in HNSCC tumor cells confers survival and invasive properties, and thereby provides a strong rationale for targeting EphB4 as novel therapy for HNSCC.
...
PMID:EphB4 provides survival advantage to squamous cell carcinoma of the head and neck. 1661 13

Proline oxidase (POX), often considered a 'housekeeping enzyme' might play an important role in apoptosis. We have shown that POX generated proline-dependent reactive oxygen species (ROS), specifically superoxide radicals, and induced apoptosis through the mitochondrial (intrinsic) pathway. In our current report, we used DLD-1 colorectal cancer cells stably transfected with the POX gene under the control of a tetracycline-inducible promoter and found POX-stimulated expression of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), DR5 and cleavage of caspase-8. Importantly, apoptosis measured by flow cytometry was partially inhibited by Z-IETD-FMK, a specific inhibitor of caspase-8. These findings suggest that the extrinsic (death receptor) pathway also is activated by POX. Furthermore, the mechanism of this effect on the extrinsic pathway, specifically, the induction of TRAIL by POX, may be mediated by NFAT transcription factors. Additionally, POX expression also dramatically decreased phosphorylation of MEK and ERK, and the decrease was partially reversed by expression of manganese superoxide dismutase (MnSOD). Overexpression of constitutively active form of MEK, acMEK, partially blocked POX-induced apoptosis. These findings suggest the involvement of MEK/ERK signaling and further confirm the role of ROS/superoxides in POX-induced apoptosis. Combined with previously published data, we conclude that POX may induce apoptosis through both intrinsic and extrinsic pathways and is involved in nuclear factor of activated T cells (NFAT) signaling and regulation of the MEK/ERK pathway. It is suggested that, as a nutrition factor, POX may modulate apoptosis signals induced by p53 or other anti-cancer agents and enhance apoptosis in stress situations.
...
PMID:Proline oxidase activates both intrinsic and extrinsic pathways for apoptosis: the role of ROS/superoxides, NFAT and MEK/ERK signaling. 1661 34

The epidermal growth factor (EGF) receptor (EGFR) plays an important role in the growth and progression of breast cancer. Overexpression of EGFR or the high activity of EGFR signal pathway has been related with increases in cell proliferation and a poor prognosis in patients with breast cancer. Several human breast cancer cell lines depend on estrogen for their proliferation. EGF may bypass the requirement of estrogen for the proliferation of breast cancer cells. To evaluate this hypothesis, MCF-7 breast cancer cells were stimulated with EGF and the effects on cell proliferation, signal pathways, and cell cycle progression were determined. The results demonstrate that EGF stimulation in the absence of others growth factors induced a modest effect on cell proliferation and the induction of a cellular arrest in the G(1) phase of the cell cycle. Although phosphorylation of AKT and ERK proteins were detected, this phosphorylation was insufficient to support of cell cycle progression. Cellular arrest in G(1) phase was accompanied by an increase in p21(CIP1) protein, down regulation of the BCL-2 protein, induction of caspase-8, and ARHI/NOEY2 an imprinted tumor suppressor gene. These results indicate that EGFR activation by itself is not sufficient for the proliferation of breast cancer cells and suggest the existence of a mechanism that induces apoptosis upon EGFR activation.
...
PMID:Cell death of MCF-7 human breast cancer cells induced by EGFR activation in the absence of other growth factors. 1686 4

Treatment with 1-4 microM As(2)O(3) slightly induced apoptosis in U-937 human promonocitic leukemia cells. This effect was potentiated by co-treatment with MEK/ERK (PD98059, U0126) and JNK (SP600125, AS601245) inhibitors, but not with p38 (SB203580, SB220025) inhibitors. However, no potentiation was obtained using lonidamine, doxorubicin, or cisplatin instead of As(2)O(3). Apoptosis potentiation by mitogen-activated protein kinase (MAPK) inhibitors involved both the intrinsic and extrinsic executionary pathways, as demonstrated by Bax activation and cytochrome c release from mitochondria, and by caspase-8 activation and Bid cleavage, respectively; and the activation of both pathways was prevented by Bcl-2 over-expression. Treatment with MEK/ERK and JNK inhibitors, but not with p38 inhibitors, caused intracellular glutathione (GSH) depletion, which was differentially regulated. Thus, while it was prevented by N-acetyl-L-cysteine (NAC) in the case of U0126, it behaved as a NAC-insensitive process, regulated at the level of DL-buthionine-(S,R)-sulfoximine (BSO)-sensitive enzyme activity, in the case of SP600125. The MEK/ERK inhibitor also potentiated apoptosis and decreased GSH content in As(2)O(3)-treated NB4 human acute promyelocytic leukemia (APL) cells, but none of these effects were produced by the JNK inhibitor. MEK/ERK and JNK inhibitors did not apparently affect As(2)O(3) transport activity, as measured by intracellular arsenic accumulation. SP600126 greatly induced reactive oxygen species (ROS) accumulation, while BSO and U0126 had little or null effects. These results, which indicate that glutathione is a target of MAP kinases in myeloid leukemia cells, might be exploited to improve the antitumor properties of As(2)O(3), and provide a rationale for the use of kinase inhibitors as therapeutic agents.
...
PMID:Pharmacologic inhibitors of extracellular signal-regulated kinase (ERKs) and c-Jun NH(2)-terminal kinase (JNK) decrease glutathione content and sensitize human promonocytic leukemia cells to arsenic trioxide-induced apoptosis. 1697 61


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---