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)

Ultraviolet radiation (UV) induces apoptosis and functional maturation in skin dendritic cells (DCs). However, the molecular mechanisms through which UV activates DCs have not been thoroughly investigated. In this study, we examined the mechanisms of activation and apoptosis of DCs after UV irradiation by focusing on epidermal growth factor receptor (EGFR). Our previous studies have demonstrated that in addition to cognate ligands, EGFR is also activated by UVB irradiation in cultured human skin keratinocytes in vitro and in human skin in vivo. We found for the first time in this study that UV also induces EGFR activation in cultured mouse skin DCs (XS 106 cell line) as well as mouse monocyte-derived dendritic cells (MoDCs). Pharmacological inhibition of EGFR tyrosine kinase significantly inhibits UV-induced ERK, p38, and JNK MAP kinases, and their effectors, transcription factors c-Fos and c-Jun. Inhibition of EGFR also suppresses UV-induced activation of PI3K/AKT/mTOR/S6K and NF-kappaB signal transduction pathways. Our data demonstrated that UV induces LKB1/AMPK pathway, also dependent on EGFR trans-activation. We further observed that MAPK, LKB1/AMPK, PI3K/AKT/mTOR/S6K as well as NF-kappaB activation are impaired in EGFR-/- cells compared to wide type MEF cells after UV radiation. Taken together, we conclude that UV induces multiple signaling pathways mediated by EGFR trans-activation leading to possible maturation, apoptosis and survival, and EGFR activation protects against UV-induced apoptosis in cultured mouse dendritic cells.
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PMID:EGFR activation confers protections against UV-induced apoptosis in cultured mouse skin dendritic cells. 1864 33

Population studies have revealed that treatment with the antidiabetic drug metformin significantly associates with reduced breast cancer risk. Animal studies have shown that metformin suppresses the development of mammary carcinomas in transgenic female mice carrying a HER2 oncogene, but not that of spontaneous tumors. We herein demonstrate that HER2 oncoprotein itself may represent a key cellular target involved in the anti-breast cancer actions of metformin. First, ectopical overexpression of HER2 oncogene significantly enhances metformin-induced breast cancer cell growth inhibition. Second, metformin treatment drastically downregulates HER2 protein levels (up to 85% reduction) in a dose- and time-dependent manner. Metformin-induced inhibition of HER2 take places regardless the molecular mechanism contributing to HER2 overexpression (i.e., human HER2 cDNA exogenously driven by a viral promoter and naturally occurring endogenous HER2 gene amplification). Mechanistically, metformin-induced suppression of HER2 overexpression appears to occur via direct (AMPK-independent) inhibition of p70S6K1 activity. Compound C- and small interference RNA (siRNA)-induced blockade of AMPK activity/expression fail to prevent the anti-HER2 effect of metformin while AMPK hyperactivation following exposure to the AMP analog AICAR is not sufficient to downregulate HER2 expression. HER2-positive breast cancer cells transfected with p70S6K1 siRNA become completely refractory to metformin-induced HER2 suppression. Of note, co-incubation with agents that block reactive oxygen species (ROS) production (e.g., N-acetylcysteine) dramatically enhanced the ability of metformin to decrease HER2 expression. From the perspective of chemoprevention, these findings altogether suggest that metformin might exert a protective mostly confined to the HER2-positive breast cancer subtype. From the perspective of intervention, the presence/absence of molecular hallmarks such as HER2 overexpression and/or p70S6K1 hyperactivation might dictate alternative responses in metformin-based treatment of early breast cancer. The importance of mTOR/p70S6K1-sensed ROS status at mediating the anti-oncogenic effects of metformin might represent a previously unrecognized linkage molecularly connecting its anti-aging and anti-cancer actions.
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PMID:The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells. 1910 26

The LKB1-AMPK signaling pathway serves as a critical cellular sensor coupling energy homeostasis to cell growth, proliferation, and survival. However, how tumor cells suppress this signaling pathway to gain growth advantage under conditions of energy stress is largely unknown. Here, we show that AMPK activation is suppressed in melanoma cells with the B-RAF V600E mutation and that downregulation of B-RAF signaling activates AMPK. We find that in these cells LKB1 is phosphorylated by ERK and Rsk, two kinases downstream of B-RAF, and that this phosphorylation compromises the ability of LKB1 to bind and activate AMPK. Furthermore, expression of a phosphorylation-deficient mutant of LKB1 allows activation of AMPK and inhibits melanoma cell proliferation and anchorage-independent cell growth. Our findings provide a molecular linkage between the LKB1-AMPK and the RAF-MEK-ERK pathways and suggest that suppression of LKB1 function by B-RAF V600E plays an important role in B-RAF V600E-driven tumorigenesis.
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PMID:Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. 1918 64

The isolated perfused heart is an important model in cardiovascular research. We hypothesized that the perfusion procedure per se will phosphorylate some protein kinases important in pre- and postconditioning. Isolated hearts were Langendorff-perfused for 20 min with or without an intraventricular balloon (rats and mice), or in the working heart mode (mice) and compared to non-perfused controls with respect to protein phosphorylation. Rat hearts were also perfused for 20 and 50 min in the Langendorff mode to investigate the effect of perfusion time on phosphorylation. Western blot analysis showed that perfusion per se induced a massive phosphorylation of ERK 1/2, P38-MAPK, JNK, AMPK, but decreased phosphorylation of AKT in the isolated rat and mouse heart. However, during ongoing perfusion the phosphorylation of these kinases was reduced. Langendorff-perfusion without the intraventricular balloon caused less phosphorylation of ERK 1/2, P38-MAPK and JNK, but had no effect on AMPK. In working hearts phosphorylation of kinases was similar to that of Langendorff-perfused hearts without the balloon. Our findings indicate that excising, handling and perfusion induce a time dependent phosphorylation of stress kinases. The presence of the intraventricular balloon caused the strongest phosphorylation, thus Langendorff-perfused hearts might be partly protected by the perfusion procedure if stress kinases are protective in pre- and postconditioning. This might explain conflicting results obtained with different models of both pre- and postconditioning, and the isolated heart might in some situations be suboptimal for such studies.
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PMID:Inadvertent phosphorylation of survival kinases in isolated perfused hearts: a word of caution. 1919 17

Recent evidence suggests that ovarian hormones contribute to altered function of skeletal muscle, however the signaling processes thought to regulate muscle function remain undefined in females. Thus, the purpose of this investigation is to determine if ovarian hormone status is critical for contraction-induced activation of AMPK or MAPK in skeletal muscle. Female mice were divided into two groups, ovariectomy (OVX) and SHAM, which were then subjected to in situ isometric contractile protocols. AMPK, ERK 1/2, p38, and JNK phosphorylation were measured in the control and contracting limb. In the in situ protocol, OVX muscles were significantly more resistant to fatigue compared to the SHAM animals. In addition, the muscles from OVX mice demonstrated significantly lower levels of normalized AMPK phosphorylation at rest. AMPK phosphorylation was not increased in the muscles from SHAM mice after the in situ contractile protocol, while the OVX demonstrated significant increases in AMPK phosphorylation. After contraction, normalized ERK2 phosphorylation was significantly higher in the OVX group compared to the SHAM group. Both p38 and JNK phosphorylation increased in response to contraction; but no group differences were detected. A second set of SHAM and OVX animals were subjected to fatigue stimulated under in vitro conditions. Significant increases in AMPK and ERK2 phosphorylation were detected, but no differences were found between groups. In conclusion, removal of the ovaries results in different responses to contraction-induced changes in phosphorylation of AMPK and ERK2 in female mice and suggests hormones secreted from the ovaries significantly impacts cellular signaling in skeletal muscle.
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PMID:Changes in contraction-induced phosphorylation of AMP-activated protein kinase and mitogen-activated protein kinases in skeletal muscle after ovariectomy. 1925 49

Genomic copy number aberrations and corresponding transcriptional deregulation in the cancer genome have been suggested to have regulatory roles in cancer development and progression. However, functional evaluation of individual genes from lengthy lists of candidate genes from genomic data sets presents a significant challenge. Here, we report effective gene selection strategies to identify potential driver genes based on systematic integration of genome scale data of DNA copy numbers and gene expression profiles. Using regional pattern recognition approaches, we discovered the most probable copy number-dependent regions and 50 potential driver genes. At each step of the gene selection process, the functional relevance of the selected genes was evaluated by estimating the prognostic significance of the selected genes. Further validation using small interference RNA-mediated knockdown experiments showed proof-of-principle evidence for the potential driver roles of the genes in hepatocellular carcinoma progression (i.e., NCSTN and SCRIB). In addition, systemic prediction of drug responses implicated the association of the 50 genes with specific signaling molecules (mTOR, AMPK, and EGFR). In conclusion, the application of an unbiased and integrative analysis of multidimensional genomic data sets can effectively screen for potential driver genes and provides novel mechanistic and clinical insights into the pathobiology of hepatocellular carcinoma.
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PMID:Identification of potential driver genes in human liver carcinoma by genomewide screening. 1936 92

The EGFR/PI3K/Akt/mTOR signaling pathway is activated in many cancers including glioblastoma, yet mTOR inhibitors have largely failed to show efficacy in the clinic. Rapamycin promotes feedback activation of Akt in some patients, potentially underlying clinical resistance and raising the need for alternative approaches to block mTOR signaling. AMPK is a metabolic checkpoint that integrates growth factor signaling with cellular metabolism, in part by negatively regulating mTOR. We used pharmacological and genetic approaches to determine whether AMPK activation could block glioblastoma growth and cellular metabolism, and we examined the contribution of EGFR signaling in determining response in vitro and in vivo. The AMPK-agonist AICAR, and activated AMPK adenovirus, inhibited mTOR signaling and blocked the growth of glioblastoma cells expressing the activated EGFR mutant, EGFRvIII. Across a spectrum of EGFR-activated cancer cell lines, AICAR was more effective than rapamycin at blocking tumor cell proliferation, despite less efficient inhibition of mTORC1 signaling. Unexpectedly, addition of the metabolic products of cholesterol and fatty acid synthesis rescued the growth inhibitory effect of AICAR, whereas inhibition of these lipogenic enzymes mimicked AMPK activation, thus demonstrating that AMPK blocked tumor cell proliferation primarily through inhibition of cholesterol and fatty acid synthesis. Most importantly, AICAR treatment in mice significantly inhibited the growth and glycolysis (as measured by (18)fluoro-2-deoxyglucose microPET) of glioblastoma xenografts engineered to express EGFRvIII, but not their parental counterparts. These results suggest a mechanism by which AICAR inhibits the proliferation of EGFRvIII expressing glioblastomas and point toward a potential therapeutic strategy for targeting EGFR-activated cancers.
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PMID:The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis. 1962 24

Calorie restriction (CR) improves obesity-related insulin resistance through undefined molecular mechanisms. Insulin receptor substrate (IRS)-1 serine/threonine kinases have been proposed to modulate insulin sensitivity through phosphorylation of IRS proteins. The aim of this study is to test the hypothesis that changes in the activity of IRS1 serine/threonine kinases may underlie the molecular mechanism of CR in improving insulin sensitivity. Obese and lean Zucker rats were subjected to 40% CR or allowed to feed ad libitum (AL) for 20 weeks; body weight and insulin sensitivity were monitored throughout this period. The activity of IRS1 serine/threonine kinases - including JNK, ERK, MTOR/p70(S6K) (RPS6KB1 as listed in the MGI Database), glycogen synthase kinase 3beta (GSK3B), AMPK (PRKAA1 as listed in the MGI Database), and protein kinase C (PRKCQ) in liver tissue extracts was measured by an in vitro kinase assay using various glutathione-S-transferase (GST)-IRS1 fragments as substrates, while phosphorylation of IRS1 and serine kinases was determined by western blotting using phosphospecific antibodies. CR in obese rats significantly reduced body weight and increased insulin sensitivity compared to AL controls. Serine kinase activity toward IRS1(S612) (corresponding to S616 in human IRS1) and IRS1(S632/635) (corresponding to S636/639 in human IRS1) was increased in obese rats compared to lean littermates, and was markedly decreased following CR. Concomitantly, obesity increased and CR decreased the activity of hepatic ERK and p70(S6K) against IRS1. The close association between the activity of hepatic ERK and p70(S6K) with insulin resistance suggests an important role for ERK and p70(S6K) in the development of insulin resistance, presumably via phosphorylation of IRS proteins.
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PMID:Improved insulin sensitivity by calorie restriction is associated with reduction of ERK and p70S6K activities in the liver of obese Zucker rats. 1980 85

Sepsis is characterized by systematic inflammation where oxidative damage plays a key role in organ failure. This study was designed to examine the impact of the antioxidant metallothionein (MT) on lipopolysaccharide (LPS)-induced cardiac contractile and intracellular Ca(2+) dysfunction, oxidative stress, endoplasmic reticulum (ER) stress and autophagy. Mechanical and intracellular Ca(2+) properties were examined in hearts from FVB and cardiac-specific MT overexpression mice treated with LPS. Oxidative stress, activation of mitogen-activated protein kinase pathways (ERK, JNK and p38), ER stress, autophagy and inflammatory markers iNOS and TNFalpha were evaluated. Our data revealed enlarged end systolic diameter, decreased fractional shortening, myocyte peak shortening and maximal velocity of shortening/relengthening as well as prolonged duration of relengthening in LPS-treated FVB mice associated with reduced intracellular Ca(2+) release and decay. LPS treatment promoted oxidative stress (reduced glutathione/glutathione disulfide ratio and ROS generation). Western blot analysis revealed greater iNOS and TNFalpha, activation of ERK, JNK and p38, upregulation of ER stress markers GRP78, Gadd153, PERK and IRE1alpha, as well as the autophagy markers Beclin-1, LCB3 and Atg7 in LPS-treated mouse hearts without any change in total ERK, JNK and p38. Interestingly, these LPS-induced changes in echocardiographic, cardiomyocyte mechanical and intracellular Ca(2+) properties, ROS, stress signaling and ER stress (but not autophagy, iNOS and TNFalpha) were ablated by MT. Antioxidant N-acetylcysteine and the ER stress inhibitor tauroursodeoxycholic acid reversed LPS-elicited depression in cardiomyocyte contractile function. LPS activated AMPK and its downstream signaling ACC in conjunction with an elevated AMP/ATP ratio, which was unaffected by MT. Taken together, our data favor a beneficial effect of MT in the management of cardiac dysfunction in sepsis.
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PMID:Cardiac overexpression of metallothionein rescues cardiac contractile dysfunction and endoplasmic reticulum stress but not autophagy in sepsis. 1991 57

Kidney cancer is not a single disease; it is made up of a number of cancers that occur in the kidney, each having a different histology, following a different clinical course, responding differently to therapy, and caused by a different gene. Study of the genes underlying kidney cancer has revealed that it is fundamentally a metabolic disorder. Understanding the genetic basis of cancer of the kidney has significant implications for diagnosis and management of this disease. VHL is the gene for clear cell kidney cancer. The VHL protein forms a complex that targets the hypoxia-inducible factors for ubiquitin-mediated degradation. Knowledge of this pathway provided the foundation for the development of novel therapeutic approaches now approved for treatment of this disease. MET is the gene for the hereditary form of type 1 papillary renal carcinoma and is mutated in a subset of sporadic type 1 papillary kidney cancers. Clinical trials are currently ongoing with agents targeting the tyrosine kinase domain of MET in sporadic and hereditary forms of papillary kidney cancer. BHD is the gene for the hereditary type of chromophobe kidney cancer. It is thought to be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways. Hereditary leiomyomatosis renal cell carcinoma, a hereditary form of type 2 papillary renal carcinoma, is caused by inactivation of a Krebs cycle enzyme due to mutation. Knowledge of these kidney cancer gene pathways has enabled new approaches in the management of this disease and has provided the foundation for the development of targeted therapeutics.
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PMID:Molecular diagnosis and therapy of kidney cancer. 2005 41


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