Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently discovered a novel signaling phenomenon involving a rapid and transient rise in intracellular low molecular weight iron complex(es) in activation of IkappaB kinase (IKK) in hepatic macrophages. We also showed direct treatment with ferrous iron substitutes for this event to activate IKK. The present study used this model to identify upstream kinases responsible for IKK activation. IKK activation induced by iron is abrogated by overexpression of a dominant negative mutant (DN) for transforming growth factor beta-activated kinase-1 (TAK1), NF-kappaB-inducing kinase, or phosphatidylinositol 3-kinase (PI3K) and by treatment with the mitogen-activated protein kinase (MAPK) kinase-1 (MEK1) inhibitor. Iron increases AKT phosphorylation that is prevented by DNTAK1 or DNp21ras. Iron causes ERK1/2 phosphorylation that is attenuated by DN-PI3K, prevented by DNp21ras, but unaffected by DNTAK1. Iron-induced TAK1 activity is not affected by the PI3K or MEK1 inhibitor, suggesting TAK1 is upstream of PI3K and MEK1. Iron increases interactions of TAK1 and PI3K with p21ras as demonstrated by co-immunoprecipitation and co-localization of these proteins with caveolin-1 as shown by immunofluorescent microscopy. Finally, filipin III, a caveolae inhibitor, abrogates iron-induced TAK1 and IKK activation. In conclusion, MEK1, TAK1, NF-kappa-inducing kinase, and PI3K are required for iron-induced IKK activation in hepatic macrophages and TAK1, PI3K, and p21ras physically interact in caveolae to initiate signal transduction.
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PMID:Iron causes interactions of TAK1, p21ras, and phosphatidylinositol 3-kinase in caveolae to activate IkappaB kinase in hepatic macrophages. 1717 71

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic disorder characterized by activation of fibroblasts and overproduction of extracellular matrix (ECM). Caveolin-1 (cav-1), a principal component of caveolae, has been implicated in the regulation of numerous signaling pathways and biological processes. We observed marked reduction of cav-1 expression in lung tissues and in primary pulmonary fibroblasts from IPF patients compared with controls. We also demonstrated that cav-1 markedly ameliorated bleomycin (BLM)-induced pulmonary fibrosis, as indicated by histological analysis, hydroxyproline content, and immunoblot analysis. Additionally, transforming growth factor beta1 (TGF-beta1), the well-known profibrotic cytokine, decreased cav-1 expression in human pulmonary fibroblasts. cav-1 was able to suppress TGF-beta1-induced ECM production in cultured fibroblasts through the regulation of the c-Jun N-terminal kinase (JNK) pathway. Interestingly, highly activated JNK was detected in IPF- and BLM-instilled lung tissue samples, which was dramatically suppressed by ad-cav-1 infection. Moreover, JNK1-null fibroblasts showed reduced smad signaling cascades, mimicking the effects of cav-1. This study indicates a pivotal role for cav-1 in ECM regulation and suggests a novel therapeutic target for patients with pulmonary fibrosis.
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PMID:Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis. 1717 17

Caveolae are abundant plasma membrane invaginations in airway smooth muscle that may function as preorganized signalosomes by sequestering and regulating proteins that control cell proliferation, including receptor tyrosine kinases (RTKs) and their signaling effectors. We previously demonstrated, however, that p42/p44 MAP kinase, a critical effector for cell proliferation, does not colocalize with RTKs in caveolae of quiescent airway myocytes. Therefore, we investigated the subcellular sites of growth factor-induced MAP kinase activation. In quiescent myocytes, though epidermal growth factor receptor (EGFR) was almost exclusively found in caveolae, p42/p44 MAP kinase, Grb2, and Raf-1 were absent from these membrane domains. EGF induced concomitant phosphorylation of caveolin-1 and p42/p44 MAP kinase; however, EGF did not promote the localization of p42/p44 MAP kinase, Grb2, or Raf-1 to caveolae. Interestingly, stimulation of muscarinic M(2) and M(3) receptors that were enriched in caveolae-deficient membranes also induced p42/p44 MAP kinase phosphorylation, but this occurred in the absence of caveolin-1 phosphorylation. This suggests that the localization of receptors to caveolae and interaction with caveolin-1 is not directly required for p42/p44 MAP kinase phosphorylation. Furthermore, we found that EGF exposure induced rapid translocation of EGFR from caveolae to caveolae-free membranes. EGFR trafficking coincided temporally with EGFR and p42/p44 MAP kinase phosphorylation. Collectively, this indicates that although caveolae sequester some receptors associated with p42/p44 MAP kinase activation, the site of its activation is associated with caveolae-free membrane domains. This reveals that directed trafficking of plasma membrane EGFR is an essential element of signal transduction leading to p42/p44 MAP kinase activation.
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PMID:p42/p44 MAP kinase activation is localized to caveolae-free membrane domains in airway smooth muscle. 1723 47

Angiogenesis, the development of new blood vessels from preexisting capillary, is required for tumor growth and metastasis. The process is not fully understood yet, but involves endothelial cell proliferation, migration and differentiation. Recently, we have shown that overexpression of caveolin-1, a putative transformation suppressor gene, inhibits VEGFR-2 and MEK-1-mediated mitogenic signal to the nucleus. Conversely, angiogenic activators suppress caveolin-1 expression in endothelial cells. However, whether caveolin-1 expression affects endothelial cell proliferation is not clear. In the present study, we infect human endothelial cells with adenovirus expressing caveolin-1 and show that transient overexpression of caveolin-1 dramatically inhibits the proliferation of human endothelial cells. Consistent with caveolin-1 functioning as an inhibitor for protein kinases, overexpression of caveolin-1 inhibits the activity of VEGFR-2 (KDR) and down-stream p42/44 MAP kinase. Furthermore, overexpression of caveolin-1 prevents VEGF-induced down-regulation of the cyclin-dependent kinase inhibitor p27(kip1) and Rb phosphorylation, and subsequently arrests endothelial cells in the G(0)/G(1) phase. Thus, our results suggest that caveolin-1, as a negative regulator of endothelial cell proliferation, may be a potential target for the control of angiogenesis.
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PMID:Overexpression of caveolin-1 inhibits endothelial cell proliferation by arresting the cell cycle at G0/G1 phase. 1724 31

The same dietary component, such as fat or phytochemicals in plant foods, can have an opposite effect on breast cancer risk if exposed in utero through a pregnant mother or at puberty. Dietary exposures during pregnancy often have similar effects on breast cancer risk among mothers and their female offspring. High fat intake and obesity are illustrative examples: excessive pregnancy weight gain that increases high birth weight is associated with increased breast cancer risk among mothers and daughters. High body weight during childhood is inversely linked to later breast cancer risk. The main reason why the age when dietary exposures occur determines their effect on breast cancer risk likely reflects the extensive programming of the mammary gland during fetal life and subsequent reprogramming at puberty and pregnancy. Programming is a series of epigenetic/transcriptional modifications in gene expression that can be influenced by changes in the hormonal environment induced, for example, by diet. Because epigenetic modifications are inherited by daughter cells, they can persist throughout life if they occur in mammary stem cells or uncommitted mammary myoepithelial or luminal progenitor cells. Our results indicate that the estrogen receptor (ER), mitogen-activated protein kinase (MAPK), and the tumor suppressors BRCA1, p53, and caveolin-1 are among the genes affected by diet-induced alterations in programming/reprogramming. Consequently, mammary gland morphology may be altered in a manner that increases or reduces susceptibility to malignant transformation, including an increase/reduction in cell proliferation, differentiation, and survival, or in the number of terminal end buds (TEBs) or pregnancy-induced mammary epithelial cells (PI-MECs) that are the sites where breast cancer is initiated. Thus, dietary exposures during pregnancy and puberty may play an important role in determining later risk by inducing epigenetic changes that modify vulnerability to breast cancer.
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PMID:Timing of dietary estrogenic exposures and breast cancer risk. 1726 53

The cellular functions regulated by 17beta-estradiol (E2) start after the hormone binds to its receptors (i.e., ERalpha and ERbeta). These act as ligand-dependent transcription factor transactivating target genes. In addition, E2 induces non-genomic actions, whose activation is triggered by a fraction of the ERs localized at the plasma membrane. Palmitoylation allows ERalpha to localize at the plasma membrane, to associate with caveolin-1, and, upon E2 stimulation, to activate rapid signals relevant for cell proliferation. The existence of a mechanism, which allows ERbeta localization at the plasma membrane and its putative role in anti-proliferative E2 effects is completely unknown. Here, the susceptibility of ERbeta to undergo palmitoylation and the role played by this process has been analyzed in DLD-1 containing endogenous ERbeta or in HeLa cells transiently transfected with ERbeta or ERalpha expression vectors. As for ERalpha, palmitoylation is necessary for ERbeta localization at the plasma membrane and its association with caveolin-1 but, in contrast to ERalpha, the E2 binding increases ERbeta association with caveolin-1 and the p38 member of MAPK family. Moreover, the palmitoyl acyl transferase (PAT) inhibitor blocks the ability of ERbeta-E2 complex to activate p38 impairing the receptor-dependent activation of downstream proapoptotic cascade (i.e., caspase-3 activation and poly(ADP-ribose)polymerase (PARP) cleavage). Consequently, palmitoylation must be considered to be a molecular device for ERbeta, which allows these receptors to interact with the plasma membrane and to regulate E2-induced non-genomic functions relevant to the anti-proliferative effect of this hormone.
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PMID:Role of ERbeta palmitoylation in the inhibition of human colon cancer cell proliferation. 1739 84

Caveolin-1 (Cav-1) is an integral transmembrane protein and a critical component in interactions of integrin receptors with cytoskeleton-associated and signaling molecules. Since integrin-mediated cell adhesion generates signals conferring radiation resistance, we examined the effects of small interfering RNA-mediated knockdown of Cav-1 alone or in combination with beta1-integrin or focal adhesion kinase (FAK) on radiation survival and proliferation of pancreatic carcinoma cell lines. Irradiation induced Cav-1 expression in PATU8902, MiaPaCa2 and Panc1 cell lines. The cell lines showed significant radiosensitization after knockdown of Cav-1, beta1-integrin or FAK and cholesterol depletion by beta-cyclodextrin relative to nonspecific controls. Under knockdown conditions, proliferation of non-irradiated and irradiated cells was significantly attenuated relative to controls. These findings correlated with changes in expression or phosphorylation of Akt, glycogen synthase kinase 3beta, Paxillin, Src, c-Jun N-terminal kinase and mitogen-activated protein kinase. Analysis of DNA microarray data revealed a Cav-1 overexpression in a subset of pancreatic ductal adenocarcinoma samples. The data presented show, for the first time, that disruption of interactions of Cav-1 with beta1-integrin or FAK affects radiation survival and proliferation of pancreatic carcinoma cells and suggest that Cav-1 is critical to these processes. These results indicate that strategies targeting Cav-1 may be useful as an approach to improve conventional therapies, including radiotherapy, for pancreatic cancer.
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PMID:Human pancreatic tumor cells are sensitized to ionizing radiation by knockdown of caveolin-1. 1747 Dec 32

It has been reported that cellular prion protein (PrPc) is enriched in caveolae or caveolae-like domains with caveolin-1 (Cav-1) participating to signal transduction events by Fyn kinase recruitment. By using the Glutathione-S-transferase (GST)-fusion proteins assay, we observed that PrPc strongly interacts in vitro with Cav-1. Thus, we ascertained the PrPc caveolar localization in a hypothalamic neuronal cell line (GN11), by confocal microscopy analysis, flotation on density gradient, and coimmunoprecipitation experiments. Following the anti-PrPc antibody-mediated stimulation of live GN11 cells, we observed that PrPc clustered on plasma membrane domains rich in Cav-1 in which Fyn kinase converged to be activated. After these events, a signaling cascade through p42/44 MAP kinase (Erk 1/2) was triggered, suggesting that following translocations from rafts to caveolae or caveolae-like domains PrPc could interact with Cav-1 and induce signal transduction events.
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PMID:Cellular prion protein and caveolin-1 interaction in a neuronal cell line precedes Fyn/Erk 1/2 signal transduction. 1748 19

This study was designed to provide a direct demonstration of the importance of caveolin-1 in the compartmentalization of estrogen receptor beta (ERbeta) to the membrane, thus allowing 7beta-estradiol (E2) to control vitamin D receptor (VDR) transcription and expression. Our strategy was to obtain cell lines expressing different levels of caveolin-1. To this end, we transfected human embryonic kidney 293 cells with a caveolin-1-expressing vector and obtained three cell-line variants: one expressing high amounts of caveolin-1 (clone A), one expressing low amounts of caveolin-1 (clone B), and one expressing high amounts of the nonfunctional P132L caveolin-1 mutant (clone C), and compared these with parental (wild-type, WT) cells expressing negligible levels of caveolin-1. In clone A, ERbeta colocalized to membrane preparations and E2 treatment induced significant ERK 1/2 phosphorylation and enhanced VDR expression. In clones B and C and the WT, ERbeta did not localize to membrane preparations and E2 treatment was ineffective at inducing VDR upregulation associated with ERK 1/2 phosphorylation. Luciferase reporter gene expression assays showed that the human VDR promoter is only highly responsive to E2 treatment in clone A, except in the presence of the ER-specific inhibitor ICI182 780. Cotransfection of clone A with the VDR promoter and several mutants of MAPK kinase (MEK) demonstrated that the constitutively active form of MEK significantly increases VDR promoter activation, while the catalytically inactive construct is ineffective in this regard. In clone A cells transfected with an activation protein-1 (AP-1)-luciferase construct, E2 significantly upregulated the promoter activity, while ICI182 780 completely eliminated this E2-mediated effect. Clone A cells transfected with a VDR promoter bearing a targeted mutation towards the AP-1 site showed reduced E2-mediated activation of luciferase activity. Taken together, our data confirm the importance of caveolin-1 in the association of ERbeta to the membrane caveolae, allowing ERK 1/2 phosphorylation and upregulation of VDR.
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PMID:Association of estrogen receptor beta with plasma-membrane caveola components: implication in control of vitamin D receptor. 1755 31

Clinical use of human immunodeficiency virus protease inhibitors such as ritonavir may be associated with cardiovascular disease. The objective of this study was to determine the effects and molecular mechanisms of ritonavir on cholesterol efflux from human macrophage-derived foam cells, which is a critical factor of atherogenesis. Human THP-1 monocytes and peripheral blood mononuclear cells were preincubated with acetylated low-density lipoprotein and [(3)H]cholesterol to form foam cells, which were then treated with apolipoprotein A-I for cholesterol efflux assay. A clinically relevant concentration of ritonavir (15 mumol/L) significantly reduced cholesterol efflux from THP-1 and peripheral blood mononuclear cells to apolipoprotein A-I by 30 and 29%, respectively, as compared with controls. In addition, ritonavir significantly decreased the expression of scavenger receptor B1 and caveolin-1, whereas it significantly increased superoxide anion production and activated extracellular signal-regulated kinase (ERK) 1/2 in macrophages. Mitochondrial membrane potential was significantly reduced, whereas NADPH oxidase subunits were increased in ritonavir-treated macrophages. Consequently, the antioxidant seleno-l-methionine, the specific ERK1/2 inhibitor PD98059, or infection of a recombinant adenovirus encoding the dominant-negative form of ERK2 effectively blocked ritonavir-induced decrease of cholesterol efflux. Therefore, human immunodeficiency virus protease inhibitor ritonavir significantly inhibits cholesterol efflux from macrophages, which may be mediated by mitochondrial dysfunction, oxidative stress, ERK1/2 activation, and down-regulation of scavenger receptor B1 and caveolin-1.
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PMID:Human immunodeficiency virus protease inhibitor ritonavir inhibits cholesterol efflux from human macrophage-derived foam cells. 1787 77


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