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)

CD44 has diverse functions in cell-cell and cell-matrix interactions and may be a determinant of metastatic and invasive behaviour in carcinomas. The immunohistochemical expression of CD44 in a series of 110 colorectal carcinomas and 25 adenomas was examined using the monoclonal mouse anti-human phagocytic glycoprotein-1, CD44 (clone DF 1485) in correlation with the expression of basement membrane (BM) antigens (type IV collagen, laminin), fibronectin, cathepsin D, p53, Rb, bcl-2, c-erbB-2, EGFR, proliferation indices (Ki-67, PCNA) and with other conventional clinicopathological variables. In adenomas, low CD44 expression (<10% of neoplastic cells) was present in 16%, moderate (10-50% of neoplastic cells) in 52% and extensive (>50% of neoplastic cells) in 32% of cases. In carcinomas, low CD44 expression was found in 14.5%, moderate in 28.2% and extensive in 57.30%. Although the CD44 expression was higher in carcinomas than in adenomas, we found no statistically significant difference between these two groups. CD44 expression in carcinomas was positively correlated with tumour size (P=0.018), tumour cells cathepsin D (P=0.022), stromal cell cathepsin D (P=0.003) and Rb protein (P=0.021). An inverse correlation was observed between CD44 and the anti-apoptotic protein expression bcl-2 in adenocarcinomas (P=0.039) and in adenomas (P=0.021). These data suggest that CD44 may be involved in the process of invasion and metastasis, probably with the cooperation of cathepsin D. Its expression may be an indicator of poor prognosis in colorectal adenocarcinomas.
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PMID:Glycoprotein CD44 expression in colorectal neoplasms. An immuno-histochemical study including correlation with cathepsin D, extracellular matrix components, p53, Rb, bcl-2, c-erbB-2, EGFR and proliferation indices. 1007 Dec 34

Tissue factor pathway inhibitor-2 (TFPI-2) is a 32 kDa serine protease inhibitor found at high levels in extracellular matrix. Recombinant human TFPI-2 has recently been shown to be a strong inhibitor of trypsin, plasmin, plasma kallikrein, and factor XIa amidolytic activity. Earlier studies in our laboratory showed that the expression of TFPI-2 is lost during tumor progression in human gliomas. We stably transfected this protease inhibitor in multiform glioblastoma cell line (SNB-19) and in low-grade glioma cell line (Hs683) in sense and antisense orientation respectively. This confirmed that the upregulation/down-regulation of TFPI-2 plays a significant role in the invasive behavior of human gliomas both in vitro and in vivo models. Collectively, these results suggested an idea to determine whether TFPI-2 is necessary for cell survival and inhibition of tumor formation in nude mice, due to apoptosis of intracerebrally injected SNB-19 cells. In the present study we determined p-ERK levels and found that they are decreased in TFPI-2 over-expressed clones (SNB-19) and increased in TFPI-2 down-regulated clones (Hs683). We also checked the levels of BAX/BCl-2, caspases (for e.g., 9, 7, 3, 8), PARP, cytochrome-c and Apaf-1. Moreover, the increase of apoptosis in vitro is associated with increased and decreased expression of apoptotic protein BAX in sense clones (SNB-19) and antisense clones (Hs683) respectively, when compared to controls and vice versa with Bcl-2 the anti-apoptotic protein. Caspases (9, 7 and 3), cytochrome-c, Apaf-1 and PARP levels are increased in SNB-19 and decreased in Hs683. Caspase 8 was not expressed in either cell line. Caspases 9 and 3 activity assay revealed higher activity in sense clones (SNB-19) but lesser in antisense clones (Hs683) compared to controls. This is the first report of TFPI-2 playing a novel role in cell survival in human gliomas.
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PMID:A novel role of tissue factor pathway inhibitor-2 in apoptosis of malignant human gliomas. 1149 41

Bcl-2 family proteins play a critical role in the regulation of cell survival by controlling the activation of the cell death executing caspase machinery. Recent work demonstrated that they also provide a link between growth factor signaling and cell survival control. Raf-1 has been identified initially as an essential component of the mitogenic Ras-Raf-MEK-ERK cascade. However, expression of oncogenic Raf-1 also efficiently suppresses apoptotic cell death. This process requires mitochondrial translocation of Raf-1 which can be achieved either by co-expression of the anti-apoptotic protein Bcl-2 or by fusion with the transmembrane domain of the yeast outer mitochondrial membrane protein Mas 70p. It is currently unclear how mitochondrial Raf-1 prevents apoptosis. One possible mechanism involves the phosphorylation of the pro-apoptotic protein Bad resulting in the restoration of Bcl-2 function. Alternatively, the role of Bcl-2 could be limited to the mitochondrial translocation of Raf-1 and survival signaling by Raf-1 is Bcl-2 independent. To test for the mutual requirement of Raf-1 and Bcl-2 in apoptosis suppression the individual proteins were singly tested for survival activity in a genetic background which precludes the expression of the other. The results obtained in these studies demonstrate that ablation of Raf-1 or Bcl-2 expression in fibroblast cells significantly increases the sensitivity towards doxorubicin induced cell death. Reversion of the mutant phenotype could be achieved in either case by introducing a functional bcl-2 gene or a mitochondria targeted version of oncogenic Raf-1, demonstrating that each protein by itself is sufficient to confer protection. Our data thus suggest the existence of two separate pathways of survival signaling at the mitochondria controlled either by Bcl-2 or by Raf-1.
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PMID:Independent control of cell survival by Raf-1 and Bcl-2 at the mitochondria. 1152 Nov 92

Retinal pigmented epithelium (RPE) cells are of central importance in the maintenance of neural retinal function. RPE cell apoptosis is responsible for the development of a variety of retinal degeneration. The role of FGF2 was investigated on RPE cell proliferation and apoptosis in vitro. In the absence of serum, RPE cells died by apoptosis, while the addition of FGF2 greatly reduces apoptosis over a 7-day culture period. This is due to an autocrine loop involving secretion of endogenous FGF1 in the mechanism that govern FGF2-induced resistance to apoptosis. FGF2 induces long-term activation of FGFR1 and ERK1/2, and production of the anti-apoptotic protein BcL-x. Because FGF1 has no classical signal sequence to direct its secretion, we investigated the effects of FGF1 secretion on RPE proliferation and apoptosis in the absence of exogenous FGF2. Forced secretion of endogenous FGF1 by adding a signal peptide to the FGF1 molecule induces FGF1 secretion and cell proliferation in the presence of serum, while in FGF1 stops to be secreted and cell die in the absence of serum. Conversely, in cells cultured in the presence of serum, FGF1 without signal peptide is not secreted, but is secreted and rescue RPE cell from apoptosis when cells are cultured without serum. Thus, the proliferation and survival activities of endogenous FGF1 depend on the secretion of FGF1 which is determined by the cell environment.
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PMID:[Control of the intracellular signaling induced by fibroblast growth factors (FGF) over the proliferation and survival of retinal pigment epithelium cells: example of the signaling regulation of growth factors endogenous to the retina ]. 1172 20

293 kidney embryonic cells feature very low levels of the anti-apoptotic protein PED. In these cells, expression of PED to levels comparable with those occurring in normal adult cells inhibits apoptosis induced by growth factor deprivation and by exposure to H(2)O(2) or anisomycin. In PED-expressing 293 cells (293(PED)), inhibition of apoptosis upon growth factor deprivation was paralleled by decreased phosphorylation of JNK1/2. In 293(PED) cells, decreased apoptosis induced by anisomycin and H(2)O(2) was also accompanied by block of JNK1/2 and p38 phosphorylations, respectively. Impaired activity of these stress kinases by PED correlated with inhibition of stress-induced Cdc-42, MKK4, and MKK6 activation. At variance with JNK1/2 and p38, PED expression increased basal and growth factor-stimulated Ras-Raf-1 co-precipitation and MAPK phosphorylation and activity. Treatment of 293(PED) cells with the MEK inhibitor PD98059 blocked ERK1/2 phosphorylations with no effect on inhibition of JNK1/2 and p38 activities. Complete rescue of JNK and p38 functions in 293(PED) cells by overexpressing JNK1 or p38, respectively, enabled only partial recovery of apoptotic response to growth factor deprivation and anisomycin. However, simultaneous rescue of JNK and p38 activities accompanied by block of ERK1/2 fully restored these responses. Thus, PED controls activity of the ERK, JNK, and p38 subfamilies of MAPKs. PED anti-apoptotic function in the 293 cells requires PED simultaneous activation of ERK1/2 and inhibition of the JNK/p38 signaling systems by PED.
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PMID:Multiple members of the mitogen-activated protein kinase family are necessary for PED/PEA-15 anti-apoptotic function. 1179 Jul 85

Glioblastoma multiforme is the most common highly aggressive human brain cancer, and receptor tyrosine kinases have been implicated in the progression of this malignancy. We have recently identified anaplastic lymphoma kinase (ALK) as a tyrosine kinase receptor for pleiotrophin, a secreted growth factor that is highly expressed during embryonic brain development and in tumors of the central nervous system. Here we report on the contribution of pleiotrophin-ALK signaling to glioblastoma growth. We found ALK overexpressed in human glioblastoma relative to normal brain and detected ALK mRNA in glioblastoma cell lines. We reduced the endogenous ALK in glioblastoma cells by ribozyme targeting and demonstrated that this prevents pleiotrophin-stimulated phosphorylation of the anti-apoptotic protein Akt. Furthermore, this depletion of ALK reduced tumor growth of xenografts in athymic nude mice and prolonged survival of the animals because of increased apoptosis in the tumors. These findings directly implicate ALK signaling as a rate-limiting factor in the growth of glioblastoma multiforme and suggest potential utility of therapeutic targeting of ALK.
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PMID:Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth. 1180 60

The anaplastic lymphoma kinase (ALK) gene is characteristically translocated in Anaplastic Large Cell Lymphomas (ALCL) and the juxtaposition of the ALK gene to multiple partners results in its constitutive protein tyrosine kinase activity. We show here that expression of activated ALK induces the constitutive phosphorylation of Stat3 in transfected cells as well as in primary human ALCLs. Furthermore, immunohistochemical studies demonstrate that among distinct human B and T cell lymphomas, activation of Stat3 nuclear translocation is uniquely associated with ALK expression. NPM-ALK also binds and activates Jak3; however, Jak3 is not required for Stat3 activation or for cell transformation in vitro. Moreover, src family kinases are not necessary for NPM-ALK-mediated Stat3 activation or transformation, suggesting that Stat3 may be phosphorylated directly by ALK. To evaluate relevant targets of ALK-activated Stat3, we investigated the regulation of the anti-apoptotic protein Bcl-x(L) and its role in cell survival in NPM-ALK positive cells. NPM-ALK expression caused enhanced Bcl-x(L) transcription, largely mediated by Stat3. Increased expression of Bcl-x(L) provided sufficient anti-apoptotic signals to protect cells from treatment with specific inhibitors of the Jaks/Stat pathway or the Brc-Abl kinase. These studies support a pathogenic mechanism whereby stimulation of anti-apoptotic signals through activation of Stat3 contributes to the successful outgrowth of ALK positive tumor cells.
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PMID:Anaplastic lymphoma kinase (ALK) activates Stat3 and protects hematopoietic cells from cell death. 1185 Aug 21

Members of the Bcl-2 family of proteins function either to promote or to repress apoptosis. Bcl-2 has been mainly localised to the mitochondria and acts predominantly upstream of cytochrome c release in its prevention of apoptosis. Little is known about the function of Bcl-2 independent of an apoptotic stimulus. Here we demonstrate that inducible overexpression of the anti-apoptotic protein Bcl-2 in a PC12 Tet-on- cell line up-regulates mRNA expression and leads to phosphorylation of c-Jun at Ser73 via the ERK pathway in a time and concentration dependent manner. Phosphorylation of c-Jun was inhibited by the addition of the selective ERK inhibitor PD 98059. No activation of the stress-activated protein kinases JNK and p38 could be detected. This is the first evidence of a direct activation of the Ras-Raf-MAPK cascade by an anti-apoptotic protein. We propose that the selective activation of Ras, the ERK pathway and the subsequent phosphorylation of c-Jun contribute to the anti-apoptotic action of Bcl-2.
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PMID:Bcl-2 up-regulates ha-ras mRNA expression and induces c-Jun phosphorylation at Ser73 via an ERK-dependent pathway in PC 12 cells. 1249 45

MAP kinase pathways comprise a group of parallel protein phosphorylation cascades, which are involved in signaling triggered by a variety of stimuli. Previous findings suggested that the ERK and the JNK pathways have opposing roles in regulating proliferation and survival or apoptosis and that apoptosis can be promoted by inhibiting the ERK pathway or by activation of the JNK pathway. In order to test this hypothesis and explore whether it can be exploited as a strategy for killing human cancer cells, we used gene transfer experiments with a range of cancer cell lines. We expressed the catalytic fragment of human MEKK1 to activate JNK and the Ras-binding domain (RBD) of Raf-1 to inhibit the Ras-ERK pathway. In addition, we designed several RBD-MEKK1 fusion proteins aiming to simultaneously activate the JNK and block the ERK pathway. We found that the MEKK1 proteins as well as the RBD alone could reduce colony formation in all cell lines. The survival time of MEKK1-expressing cells depended on the cell line. In HeLa cells, survival could be prolonged by inhibition of caspases but not by coexpression of the anti-apoptotic protein Bcl-2. Due to a lower kinase activity the RBD-MEKK1 fusion proteins were less effective in apoptosis induction than the MEKK1 kinase domain alone. Using mutant forms of Ras and Raf-1 we could show that the reduced kinase activity of RBD-MEKK1 fusion proteins was caused by binding to the Ras protein. The expression of lethal doses of MEKK1 resulted in a strong activation of all three major MAP kinase families JNK, ERK, and p38. Blocking these pathways either by coexpressing a dominant negative form of MKK4 or with inhibitors of MEK or p38 failed to inhibit apoptosis. This suggests that MEKK1 induces apoptosis by causing a general deregulation of MAP kinase signaling rather than by the activation of a single pathway.
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PMID:The kinase domain of MEKK1 induces apoptosis by dysregulation of MAP kinase pathways. 1256 21

We recently identified TL1A, an endothelium-derived T cell costimulator and a ligand for tumor necrosis factor receptor superfamily members DR3 and decoy receptor 3. To elucidate the signaling events triggered by TL1A-DR3 interaction and to understand the molecular mechanisms regulating DR3-mediated apoptosis, we have studied the effect of TL1A and an agonistic DR3 monoclonal antibody in human erythroleukemic TF-1 cells, which express DR3 endogenously. TL1A induced the formation of a DR3 signaling complex containing TRADD, TRAF2, and RIP and activated the NF-kappaB and the ERK, JNK, and p38 mitogen-activated protein kinase pathways. However, TL1A or an agonistic DR3 monoclonal antibody did not induce apoptosis in these cells nor were there detectable levels of FADD or procaspase-8 seen in the signaling complex. Interestingly, DR3-mediated apoptosis was induced in TF-1 cells in the presence of a NF-kappaB pathway-specific inhibitor but not in the presence of mitogen-activated protein kinase inhibitors, either alone or in combination, suggesting that DR3-induced NF-kappaB activation was responsible for resistance to apoptosis in these cells. Consistent with this, we found that TL1A significantly increased the production of c-IAP2, a known NF-kappaB-dependent anti-apoptotic protein, and that the NF-kappaB inhibitor or cycloheximide prevented its synthesis. Furthermore, inhibition of c-IAP2 production by RNA interference significantly sensitized TF-1 cells to TL1A-induced apoptosis. Our study identifies a molecular mechanism by which TL1A and DR3 regulate cell fate in TF-1 cells.
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PMID:TL1A-induced NF-kappaB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells. 1288 79


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