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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent evidence has implied that disruption of a limited number of defined cellular pathways is necessary and sufficient for neoplastic conversion of a variety of normal human cell types in tissue culture. We show instead that malignancy in such models results from an iterative process of clonal selection in vitro and/or in vivo. Normal human fibroblasts underwent malignant transformation after transduction with telomerase, cyclin-dependent kinase 4, dominant-negative p53, and activated Ras or MEK. Furthermore, culture conditions favoring overgrowth resulted in clonal selection, which with added Ras or MEK oncogenes led to the emergence of tumorigenic clones. Such tumors showed variable degrees of malignancy with some even exhibiting metastasis. SV40 small t antigen (ST) has been reported to be necessary and sufficient to convert human fibroblasts with these pathway aberrations to a polyclonal tumor. However, we observed that clonal tumors emerged even with ST addition. Genomic instability was markedly increased by p53 and Rb pathway abrogation. Under the same conditions, fibroblasts with these alterations failed to induce tumors, implying that genomic instability may be necessary but not sufficient for malignant transformation. These findings indicate that the minimum number of events required for malignant transformation of human fibroblasts is greater than has been enumerated by such oncogene addition strategies and support a stochastic cancer progression model initiated by four defined cellular alterations.
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PMID:Clonal selection in malignant transformation of human fibroblasts transduced with defined cellular oncogenes. 1831 5

Activation of the Raf/MEK/ERK pathway, often by gain-of-function mutations of RAS or RAF, is observed in many human cancers. The extracellular signal-regulated kinase (ERK) pathway is required for the proliferation of cancer cell lines harboring activating BRAF or, to a lesser extent, activating RAS mutations. It is still unclear, however, whether the pathway is required in vivo for tumor development, particularly in tumors in which B-Raf is not mutationally activated. During embryonic development, B-Raf is essential for angiogenesis in the placenta. To address the question of whether B-Raf contributed to tumor angiogenesis in vivo we conditionally ablated B-Raf in a model of pancreatic islet carcinoma driven by the functional inactivation of tumor suppressors (RIP1Tag2), which critically depends on angiogenesis for growth. We find that B-Raf is dispensable for the proliferation of tumor cells in culture, but necessary for ERK activation and for the expression of angiogenic factors by tumor cells in vivo and in vitro. In vivo, these defects result in the formation of hollow tumors with decreased vessel density and strongly reduced proliferation. The progression from adenoma to carcinoma is also significantly impaired. Thus, endogenous B-Raf contributes to the development of RIP1Tag2 tumors by supporting the stromal response and tumor progression.
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PMID:B-Raf is required for ERK activation and tumor progression in a mouse model of pancreatic beta-cell carcinogenesis. 1849 Sep 24

TIMP-1 (Tissue inhibitor of matrix metalloproteinase-1) is typically associated with inhibition of matrix metalloproteinases (MMP) induced invasion. However, TIMP-1 is overexpressed in many malignancies and is associated with poor prognosis in breast cancer. The mechanisms by which TIMP-1 promotes tumorigenesis are unclear. Reduced levels of TIMP-1 mediated by shRNA in MDA-MB-231 breast cancer cells had no effect on cellular physiology in vitro or tumor growth in SCID mice compared to vector control MDA-MB-231 cells. However, overexpression of TIMP-1 in MDA-MB-231 cells resulted in inhibition of cell invasion and enhanced phosphorylation of p38 MAPK and AKT in vitro. Additionally, treatment of parental MDA-MB-231 cells with purified TIMP-1 protein led to activation of p38 MAPK and MKK 3/6. cDNA array analysis demonstrated that high expression of TIMP-1 in MDA-MB-231 cells resulted in alterations in expression of approximately 200 genes, 1.5 fold or greater compared to vector control cells (P < 0.1). Real-time RT-PCR confirmed changes in expression of several genes associated with cancer progression including DAPK1, FGFR4 and MAPK13. In vivo, high TIMP-1 expression induced tumor growth in SCID mice compared to vector control cells and increased tumor vessel density. Affymetrix array analysis of vector control and TIMP-1 MDA-MB-231 xenograft tumors revealed that TIMP-1 altered expression of approximately 600 genes in vivo, including MMP1, MMP13, S100A14, S100P, Rab25 and ID4. These combined observations suggest that the effects of TIMP-1 differ significantly in a 2-D environment compared to the 3-D environment and that TIMP-1 stimulates tumor growth.
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PMID:TIMP-1 overexpression promotes tumorigenesis of MDA-MB-231 breast cancer cells and alters expression of a subset of cancer promoting genes in vivo distinct from those observed in vitro. 1878 47

Signaling by the receptor for stem cell factor (SCF), c-Kit, is of major importance for hematopoiesis, melanogenesis and reproduction, and the biological responses are commonly proliferation and cell survival. Thus, constitutive activation due to c-Kit mutations is involved in the pathogenesis of several forms of cancer, e.g. leukemias, gastrointestinal stromal tumors and testicular tumors. Tumor survival requires oxygen supply through induced neovascularization, a process largely mediated by the vascular endothelial growth factor (VEGF), a prominent target of the transcription factors hypoxia-inducible factor-1 (HIF-1) and HIF-2. Using Affymetrix microarrays we have identified genes that are upregulated following SCF stimulation. Interestingly, many of the genes induced were found to be related to a hypoxic response. These findings were corroborated by our observation that SCF stimulation of the hematopoietic cell lines M-07e induces HIF-1alpha and HIF-2alpha protein accumulation at normoxia. In addition, SCF-induced HIF-1alpha was transcriptionally active, and transcribed HIF-1 target genes such as VEGF, BNIP3, GLUT1 and DEC1, an effect that could be reversed by siRNA against HIF-1alpha. We also show that SCF-induced accumulation of HIF-1alpha is dependent on both the PI-3-kinase and Ras/MEK/Erk pathways. Our data suggest a novel mechanism of SCF/c-Kit signaling in angiogenesis and tumor progression.
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PMID:Stem cell factor induces HIF-1alpha at normoxia in hematopoietic cells. 1883 62

We previously described the novel zinc finger protein ZKSCAN3 as a new "driver" of colon cancer progression. To investigate the underlying mechanism and because the predicted structural features (tandem zinc fingers) are often present in transcription factors, we hypothesized that ZKSCAN3 regulates the expression of a gene(s) favoring tumor progression. We employed unbiased screening to identify a DNA binding motif and candidate downstream genes. Cyclic amplification and selection of targets using a random oligonucleotide library and ZKSCAN3 protein identified KRDGGG as the DNA recognition motif. In expression profiling, 204 genes were induced 2-29-fold, and 76 genes reduced 2-5-fold by ZKSCAN3. To enrich for direct targets, we eliminated genes under-represented (<3) for the ZKSCAN3 binding motif (identified by CAST-ing) in 2 kilobases of regulatory sequence. Up-regulated putative downstream targets included genes contributing to growth (c-Met-related tyrosine kinase (MST1R), MEK2; the guanine nucleotide exchanger RasGRP2, insulin-like growth factor-2, integrin beta 4), cell migration (MST1R), angiogenesis (vascular endothelial growth factor), and proteolysis (MMP26; cathepsin D; PRSS3 (protease serine 3)). We pursued integrin beta 4 (induced up to 6-fold) as a candidate target because it promotes breast cancer tumorigenicity and stimulates phosphatidyl 3-kinase implicated in colorectal cancer progression. ZKSCAN3 overexpression/silencing modulated integrin beta 4 expression, confirming the array analysis. Moreover, ZKSCAN3 bound to the integrin beta 4 promoter in vitro and in vivo, and the integrin beta 4-derived ZKSCAN3 motif fused upstream of a tk-Luc reporter conferred ZKSCAN3 sensitivity. Integrin beta 4 knockdown by short hairpin RNA countered ZKSCAN3-augmented anchorage-independent colony formation. We also demonstrate vascular endothelial growth factor as a direct ZKSCAN3 target. Thus, ZKSCAN3 regulates the expression of several genes favoring tumor progression including integrin beta 4.
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PMID:Unbiased screening for transcriptional targets of ZKSCAN3 identifies integrin beta 4 and vascular endothelial growth factor as downstream targets. 1894 Aug 3

Although the health benefits of dietary antioxidants have been extensively studied, their potential negative effects remain unclear. L-Ascorbic acid 6-palmitate (AAP), a synthetic derivative of ascorbic acid (AA), is widely used as an antioxidant and preservative in foods, vitamins, drugs, and cosmetics. Previously, we found that AA exerted an antitumor effect by protecting inhibition of gap-junctional intercellular communication (GJIC), which is closely associated with tumor progression. In this study, we examined whether AAP, an amphipathic derivative of AA, has chemopreventive effects using a GJIC model. AAP and AA exhibited dose-dependent free radical-scavenging activities and inhibited hydrogen peroxide (H(2)O(2))-induced intracellular reactive oxygen species (ROS) production in normal rat liver epithelial cells. Unexpectedly, however, AAP did not protect against the inhibition of GJIC induced by H(2)O(2); instead, it inhibited GJIC synergistically with H(2)O(2). AAP inhibited GJIC in a dose-dependent and reversible manner. This inhibitory effect was not due to the conjugated lipid structure of AAP, as treatment with palmitic acid alone failed to inhibit GJIC under the same conditions. The inhibition of GJIC by AAP was restored in the presence of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor U0126, but not in the presence of other signal inhibitors and antioxidant (PKC inhibitors, EGFR inhibitor, NADPH oxidase inhibitor, catalase, vitamin E, or AA), indicating the critical involvement of MEK signaling in the GJIC inhibitory activity of AAP. Phosphorylation of ERK and connexin 43 (Cx43) was observed following AAP treatment, and this was reversed by U0126. These results suggest that the AAP-induced inhibition of GJIC is mediated by the phosphorylation of Cx43 via activation of the MEK-ERK pathway. Taken together, our results indicate that AAP has a potent carcinogenic effect, and that the influence of dietary antioxidants on carcinogenesis may be paradoxical.
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PMID:Ascorbic acid 6-palmitate suppresses gap-junctional intercellular communication through phosphorylation of connexin 43 via activation of the MEK-ERK pathway. 1902 67

Lung metastasis is one of the important characteristics of salivary adenoid cystic carcinoma (SACC). Although activation of extracellular signal-regulated kinase 1/2 (ERK1/2) pathway may be associated with cancer progression in some malignant tumors, its roles in lung metastasis of SACC remains unclear. We examined the expression of activated ERK1/2 in SACC-LM with high lung-metastatic rate and SACC-83 with low lung-metastatic rate, as well as in the tissues from lung-metastatic and non-metastatic groups of SACC patients. Western blot analysis indicated that SACC-LM exhibited higher expression of activated ERK1/2 than SACC-83. Similarly, immunohistochemistry showed that expression of activated ERK1/2 was detected in 73% (8/11) of the primary tissues from SACC patients with lung metastasis, while only 25% (3/12) of the primary tissues from SACC patients without lung metastasis (P<0.05). Furthermore, we examined the effects of U0126, a specific inhibitor of mitogen activated protein kinase kinase (MEK or MAPKK), on migration and invasion in SACC-LM cells, showing U0126 not only inactivated ERK1/2, but also inhibited migration and invasion of SACC-LM. The present findings suggested that the elevated expression of activated ERK1/2 may play a role in lung metastasis of salivary adenoid cystic carcinoma.
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PMID:Relationship of activated extracellular signal-regulated kinase 1/2 with lung metastasis in salivary adenoid cystic carcinoma. 1908 54

The matricellular protein CCN2 (connective tissue growth factor, CTGF) has been previously implicated in tumorigenesis. In pancreatic cancer cells, CCN2 expression occurs downstream of ras/MEK/ERK. Direct evidence that CCN2 mediates tumor progression in pancreatic cancer has been lacking. An exciting recent report by Bennewith et al. (Cancer Res 69:775-784, 2009) has used shRNA knockdown of CCN2 to illustrate that CCN2 contributes to growth of pancreatic tumor cells, both in vitro and in vivo. This report briefly summarizes these findings.
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PMID:Death of a tumor: targeting CCN in pancreatic cancer. 1926 21

TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is known to promote cancer initiation and progression and accumulates in mammary fat tissue. Effects of TCDD are mediated by the aryl hydrocarbon receptor (AhR). Physiological conditions of moderate hypoxia in breast cancer also activate another transcription factor, hypoxia-inducible factor-1 alpha (HIF-1alpha). In addition, the transcription factors p53 and the estrogen receptor alpha (ERalpha) are important key players in breast cancer progression. Here, human breast cancer cells cultured under mild hypoxic conditions were exposed to TCDD and analyzed for regulation of p53 signaling and ERalpha transactivation. Simultaneous exposure to TCDD and hypoxia resulted in a moderate but reproducible inhibition of p53 expression. Both the direct activation of the ERalpha and the transcriptional regulation of Hdm2 mediated this inhibition. As consequence the p53-mediated target gene expression (Dusp5) was reduced. Silencing of Dusp5 by simultaneous exposure of TCDD and hypoxia or by RNAi led to increased phosphorylation of ERK1/2. This increase resulted in transactivation of ERalpha and induction of ERalpha-mediated transcription of Hdm2 and SOCS3. Specificity of ERalpha-transactivation by ERK1/2 was confirmed by treatment with MAPKK-inhibitor PD98059. The combination of inhibition of functional p53 protein and induction of ERalpha signaling could serve as a model for the operational sequence of TCDD effects to prevent cell death and promote breast tumor progression.
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PMID:TCDD mediates inhibition of p53 and activation of ERalpha signaling in MCF-7 cells at moderate hypoxic conditions. 1957 57

The approval of sorafenib and active development of many other molecularly targeted agents in hepatocellular carcinoma (HCC) have presented a challenge to understand the mechanism of action of sorafenib and identify predictive biomarkers to select patients more likely to benefit from sorafenib. The preclinical study by Zhang and celleagues published this month in BMC Medicine provides preliminary evidence that baseline phosphorylated extracellular signaling-regulated kinase (pERK) may be a relevant marker to reflect the level of constitutive activation of the RAF/mitogen-activated protein kinase kinase (MEK)/ERK signaling pathway and has the potential value in predicting response to sorafenib. The clinical data from the initial single arm phase II study and preliminary report from the randomized phase III study also suggest the correlation of baseline archived tumor pERK levels and time to tumor progression in HCC patients. Whether baseline pERK will prove to be a useful predictive biomarker of response and clinical benefits for sorafenib in HCC will need to be validated in future large prospective studies.
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PMID:Predicting the response to sorafenib in hepatocellular carcinoma: where is the evidence for phosphorylated extracellular signaling-regulated kinase (pERK)? 1970 70


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