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)

Butyrate inhibits the proliferation of cancer cells, but the early molecular events initiated by butyrate have not been fully identified. Herein, butyrate is shown to affect the growth arrest and DNA damage-inducible gene 153 (GADD153) in HCT-116 human colon adenocarcinoma cells. Despite absence of any detectable cellular DNA damage, the expression of GADD153 was upregulated before several features characteristic of apoptosis appeared. Butyrate-induced upregulation of GADD153 mRNA was attenuated by actinomycin D, but apparently not by cycloheximide. In investigating possible involvement of MAPK in mediating the effect of butyrate on GADD153 mRNA expression, the extracellular regulated kinase (ERK) inhibitor PD98059, but neither the JNK inhibitor SP600125 nor the p38 MAPK inhibitor SB203580, blunted the ability of butyrate to upregulate GADD153 mRNA expression. U0126, a selective inhibitor of upstream MEK, had a similar effect as PD98059 on butyrate-induced GADD153 mRNA upregulation. Collectively, these findings suggest that butyrate caused activation of the GADD153 gene at the level of transcription involving mainly the MEK/ERK branch of the MAPK signal transduction pathway. Moreover, these molecular events were not the result of any DNA damage and occurred before several features characteristic of apoptosis became evident.
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PMID:Upregulation of GADD153 by butyrate: involvement of MAPK. 1876 67

Proteinase-activated receptor-2 (PAR2) plays pro-inflammatory roles in many organs including the gastrointestinal (GI) tract. To clarify the downstream pro-inflammatory signaling of PAR2 in the GI tract, we examined interleukin-8 (IL-8) release and the underlying cellular signaling following PAR2 stimulation in human colorectal cancer-derived HCT-15 cells and human gastric adenocarcinoma-derived MKN-45 cells. A PAR2-activating peptide, but not a PAR2-inactive scrambled peptide or a PAR1- activating peptide, caused IL-8 release in these GI epithelial cells. The PAR2-triggered IL-8 release was suppressed by inhibitors of MEK (U0126) or PI3-kinase (LY294002), and PAR2 stimulation indeed activated the downstream kinases, ERK and Akt. U0126 blocked the phosphorylation of ERK, but not Akt, and LY294002 blocked the phosphorylation of Akt, but not ERK. Together, PAR2 triggers IL-8 release via two independent signaling pathways, MEK/ERK and PI3-kinase/Akt, suggesting a role of PAR2 as a pro-inflammatory receptor in the GI tract.
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PMID:PAR2 triggers IL-8 release via MEK/ERK and PI3-kinase/Akt pathways in GI epithelial cells. 1885 73

In this report we investigate the signalling pathway activated by H(2)O(2) in human adenocarcinoma gastric cells (AGS) and we evaluate the anti-proliferative action of the natural stilbene trans-resveratrol. We demonstrate that H(2)O(2) accelerates cell growth and induces a prompt MEK1/2-ERK1/2 activation. Such events are also associated with the activation of c-Jun and its translocation into the nuclear compartment. A specific inhibitor of ERK1/2 phosphorylation by MEK1/2 (U0126) abrogates these phenomena. On the contrary, specific inhibition of JNK activity does not influence H(2)O(2)-mediated growth, suggesting that cell proliferation likely proceeds via MEK1/2-ERK1/2-Jun signalling axis. trans-Resveratrol is also able to completely suppress the increase in proliferation. We demonstrate that this property is not due to its antioxidant capacity but rather due to a specific inhibition of ERK1/2 phosphorylation by MEK1/2 and repression of c-Jun activation.
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PMID:trans-Resveratrol inhibits H2O2-induced adenocarcinoma gastric cells proliferation via inactivation of MEK1/2-ERK1/2-c-Jun signalling axis. 1903 33

Cell proliferation is regulated by integration of multiple pathways, such as MAPK, phosphatidylinositol 3'-kinase, protein kinase C, and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) signaling, determining whether the cell proceeds into cell cycle progression. Recently, we have demonstrated that a novel endogenous CaMKII-inhibitory protein, hCaMKIINalpha, suppresses tumor growth by inducing cell cycle arrest via p27 stabilization, accompanied by MEK/ERK deactivation. The data indicate a potential link between Ca(2+)/CaMKII and other signaling pathways, such as MAPK signaling. However, the detailed mechanisms of cross-talks between these important pathways on cell cycle regulation have not been specified. Here we report that CaMKII, in colon adenocarcinoma cells, activates MEK/ERK, which is responsible for the phosphorylation and subsequent proteasomal degradation of p27, thus causing the promotion of the S-G(2)/M transition of cell cycle progression. Importantly, we found that CaMKII can bind to MEK1 and that active CaMKII directly phosphorylates MEK1 in vitro, which could be abrogated by CaMKII inhibitor. Besides, ERK2 can directly interact with and phosphorylate p27. This is the first demonstration that CaMKII interplays with MEK1 and regulates p27 phosphorylation in the cell cycle progression. These findings provide mechanistic evidence for the cross-talk between CaMKII and MAPK signaling, which converges in MEK/ERK activation in the regulation of cell cycle progression.
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PMID:Ca(2+)/calmodulin-dependent protein kinase II promotes cell cycle progression by directly activating MEK1 and subsequently modulating p27 phosphorylation. 3259 55

Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a secreted antigen that induces apoptosis in putative receptor-expressing cells, including peripheral lymphocytes and natural killer (NK) cells. RCAS1 expression is associated with aggressive characteristics and poor overall survival for 15 different human malignancies. The putative RCAS1 receptor has not been isolated and the mechanism of RCAS1 apoptosis induction remains unclear. This study explores how RCAS1 is involved in apoptosis initiation. The cell lines SiSo and MCF-7, human uterine carcinoma and breast adenocarcinoma, respectively, both express RCAS1, but RCAS1 secretion is undetectable in MCF-7 cells. SiSo and MCF-7 cells were stimulated to induce RCAS1 ectodomain shedding followed by assessment of RCAS1 expression and secretion. Additionally, the RCAS1 putative receptor-expressing human chronic myelogenous leukemia cell line K562 was co-cultured with SiSo, MCF-7, or soluble RCAS1 to follow RCAS1 secretion in apoptosis initiation. RCAS1 secretion was strongly suppressed by inhibitors of metalloproteases, protein kinase C (PKC)-delta, mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK), epidermal growth factor (EGF), and G-protein-coupled receptor (GPCR). K562 apoptosis could be induced only by co-culturing with SiSo or soluble RCAS1. RCAS1 is thus secreted by ectodomain shedding, which may represent a pivotal step in RCAS1-induced apoptosis initiation.
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PMID:Receptor-binding cancer antigen expressed on SiSo cells induces apoptosis via ectodomain shedding. 2007 34

Neurotensin (NT) stimulates protein kinase D1 (PKD1), extracellular signal regulated kinase (ERK), c-Jun N-terminal Kinase (JNK), and DNA synthesis in the human pancreatic adenocarcinoma cell line PANC-1. To determine the effect of PKD1 overexpression on these biological responses, we generated inducible stable PANC-1 clones that express wild-type (WT) or kinase-dead (K618N) forms of PKD1 in response to the ecdysone analog ponasterone-A (PonA). NT potently stimulated c-Jun Ser(63) phosphorylation in both wild type and clonal derivatives of PANC-1 cells. PonA-induced expression of WT, but not K618N PKD1, rapidly blocked NT-mediated c-Jun Ser(63) phosphorylation either at the level of or upstream of MKK4, a dual-specificity kinase that leads to JNK activation. This is the first demonstration that PKD1 suppresses NT-induced JNK/cJun activation in PANC-1 cells. In contrast, PKD1 overexpression markedly increased the duration of NT-induced ERK activation in these cells. The reciprocal influence of PKD1 signaling on pro-mitogenicERK and pro-apopotic JNK/c-Jun pathways prompted us to examine whether PKD1 overexpression promotes DNA synthesis and proliferation of PANC-1 cells. Our results show that PKD1 overexpression increased DNA synthesis and cell numbers of PANC-1 cells cultured in regular dishes or in polyhydroxyethylmethacrylate [Poly-(HEMA)]-coated dishes to eliminate cell adhesion (anchorage-independent growth). Furthermore, PKD1 overexpression markedly enhanced DNA synthesis induced by NT (1-10 nM). These results indicate that PKD1 mediates mitogenic signaling in PANC-1 and suggests that this enzyme could be a novel target for the development of therapeutic drugs that restrict the proliferation of these cells.
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PMID:Induced overexpression of protein kinase D1 stimulates mitogenic signaling in human pancreatic carcinoma PANC-1 cells. 2008 6

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States, with an overall 5-year survival rate of <5%. Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is highly resistant to conventional chemotherapies, underscoring the critical need for new molecular targets for pancreatic cancer chemotherapy. The KRAS proto-oncogene is mutated in >90% of PDAC. Protein kinase Ciota (PKCiota) is required for the oncogenic Ras-mediated transformed growth of lung cancer and intestinal epithelial cells. However, little is known about the role of PKCiota in pancreatic cancer. In this study, we evaluated the expression of PKCiota in human pancreatic cancer and the requirement for PKCiota for the transformed growth and tumorigenicity of PDAC cells. We find that PKCiota is significantly overexpressed in human pancreatic cancer, and high PKCiota expression correlates with poor patient survival. Inhibition of PKCiota expression blocks PDAC cell transformed growth in vitro and tumorigenicity in vivo. Inhibition of PKCiota expression in pancreatic tumors also significantly reduces tumor angiogenesis and metastasis. Analysis of downstream PKCiota effectors implicates the Rac1-MEK/ERK1/2 signaling axis in PKCiota-mediated transformed growth and cellular invasion. Taken together, our data show a required role for PKCiota in the transformed growth of pancreatic cancer cells and reveal a novel role for PKCiota in pancreatic cancer cell metastasis and angiogenesis in vivo. Our results strongly indicate that PKCiota will be an effective target for pancreatic cancer therapy.
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PMID:Protein kinase Ciota is required for pancreatic cancer cell transformed growth and tumorigenesis. 2017 10

Apoptosis has been shown to be induced by many agents, including the clinically useful Sorafenib and K vitamins (VKs). Since few agents have activity against pancreas cancer cell growth, we evaluated the role of naturally occurring K vitamins and Sorafenib both independently and together on the growth in culture of pancreas adenocarcinoma cell lines, including PL-5, PANC-1, and MIA PaCa-2. We found that when a K vitamin was combined with Sorafenib, the dose of Sorafenib required for growth inhibition was substantially reduced. Furthermore, growth could be inhibited at doses of each VK plus Sorafenib in combination that were ineffective when used alone. This effect was seen using vitamins K1, K2, and K5. The combination of VK1 plus Sorafenib-induced apoptosis, as determined by both FACS and TUNEL staining. Phospho-ERK and Bcl-2 levels were decreased, but not levels of other bcl-2 family members. Cleavage of caspases 3 and 8, PARP and Bid were all induced by this combination. Vitamin K1 plus Sorafenib combination also resulted in elevated levels of activated c-Jun N-terminal kinase (JNK) and its substrates c-Jun and FasL. JNK inhibition partly antagonized the induction of apoptosis. Thus, combination VK1 plus Sorafenib strongly induced growth inhibition and apoptosis in pancreas cancer cells, involving both inhibition of the RAF/MEK/ERK pathway as well as activation of the JNK, c-Jun and FasL apoptotic pathway. Since both agents are available for human use, the combination is attractive for evaluation against pancreas cancer growth in vivo.
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PMID:Sorafenib combined vitamin K induces apoptosis in human pancreatic cancer cell lines through RAF/MEK/ERK and c-Jun NH2-terminal kinase pathways. 2030 Nov 94

Hypoxia is a common characteristic feature of solid tumors, and carcinoma cells are known to secrete many growth factors. These growth factors, such as vascular endothelial growth factor (VEGF), play a major role in the regulation of tumor angiogenesis and metastasis. In this study, the effect of gamma-tocotrienol, a natural product commonly found in palm oil and rice bran, on the accumulation of HIF-1alpha protein and the paracrine secretion of VEGF in human gastric adenocarcinoma SGC-7901 cell line induced by cobalt(II) chloride (as a hypoxia mimic) was investigated. These results showed that cobalt(II) chloride induced the high expression of VEGF in SGC-7901 cells at dose of 150 micromol/L for 24h. Both basal level and cobalt(II) chloride-induced HIF-1alpha protein accumulation and VEGF paracrine secretion were inhibited in SGC-7901 cells treated with gamma-tocotrienol at 60 micromol/L treatment for 24 h. U0126, a MEK1/2 inhibitor, decreased the expression of HIF-1alpha protein and the paracrine secretion of VEGF under normoxic and hypoxic conditions. In this study, gamma-tocotrienol also significantly inhibited the hypoxia-stimulated expression of phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2). The mechanism seems to involve in inhibiting hypoxia-mediated activation of p-ERK1/2, it leads to a marked decrease in hypoxia-induced HIF-1alpha protein accumulation and VEGF secretion. These data suggest that HIF-1alpha/VEGF could be a promising target for gamma-tocotrienol in an effective method of chemoprevention and chemotherapy in human gastric cancer.
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PMID:gamma-Tocotrienol modulates the paracrine secretion of VEGF induced by cobalt(II) chloride via ERK signaling pathway in gastric adenocarcinoma SGC-7901 cell line. 2045 89

Recently, to identify potential somatic mutations in genes of the epidermal growth factor receptor (EGFR) signaling pathway, the MEK1 gene mutation at exon 2 was identified. The mutant form of MEK1 leads to the constitutive activity of extracellular signal-regulated kinase (ERK)-1/2. We investigated MEK1 gene mutation status in 241 surgically treated lung adenocarcinoma cases from Nagoya City University Hospital. The presence or absence of the MEK1 mutation was analyzed by direct sequencing. EGFR mutation status was previously investigated and reported. We detected only one case (0.4%) of the MEK1 mutation (K57N) in our cohort. Total EGFR mutations were present in 101 patients (41.9%). The MEK1 mutation was mutually exclusive with B-raf, K-ras and EGFR mutations. Thus, it is a rare mutation in Japanese lung cancer patients, and of limited value for lung adenocarcinoma.
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PMID:MEK1 gene mutation in Japanese lung adenocarcinoma patients. 2147 5


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