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

Glucocorticoid hormones, retinoids, and vitamin D3 display anti-angiogenic activity in tumor-bearing animals. However, despite their in vivo effect on the tumor vasculature little is known about their mechanism of action. Here we show that the synthetic glucocorticoid dexamethasone (Dex) and retinoic acid (RA) inhibit the activation of c-Jun N-terminal kinase (JNK) and extracellular-regulated kinase (ERK) signalling pathways by the pro-angiogenic agents tumor necrosis factor and vascular endothelial growth factor in endothelial cells. In contrast, Dex and RA failed to inhibit the activation of the p38 mitogen-activated protein kinase cascade. As a number of pro-angiogenic factors activate AP-1 transcription factor via the JNK and ERK pathways, our results suggest that the antagonism with AP-1 may underlie at least partially the anti-angiogenic effect of glucocorticoids and retinoids.
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PMID:Hormone-activated nuclear receptors inhibit the stimulation of the JNK and ERK signalling pathways in endothelial cells. 1051 34

Endothelin-1 (ET-1) is a powerful mitogenic and/or anti-apoptotic peptide produced by many cancer cells. To evaluate the potential role of the endothelin system in glioblastoma we first determined the cellular distribution of the mRNA and proteins of the components of the endothelin system, preproendothelin-1 (PPET-1), endothelin-converting enzyme-1 (ECE-1), and ET(A) and ET(B) receptors in human glioblastoma tissue and glioblastoma cell lines. PPET-1, ECE-1, and ET(A) receptor were highly expressed in glioblastoma vessels and in some scattered glioblastoma areas whereas ET(B) receptor was mainly found in cancer cells. This suggests that glioblastoma vessels constitute an important source of ET-1 that acts on cancer cells via the ET(B) receptor. Four human glioblastoma cell lines expressed mRNA for all of the components of the ET-1 pathway. Bosentan, a mixed ET(A) and ET(B) receptor antagonist, induced apoptosis in these cell lines in a dose-dependent manner. Apoptosis was potentiated by Fas Ligand (APO-1L, CD95L), a pro-apoptotic peptide, only in LNZ308 cells, corresponding to the known functional Fas expression in these cell lines. LNZ308 cells also expressed the long and short forms of the cellular FLICE/caspase-8 inhibitory protein (FLIP). Bosentan and a protein kinase C inhibitor down-regulated short FLIP in these cells. ET-1 induced transient phosphorylation of extracellular signal-regulated kinase but did not induce long-term thymidine incorporation in LNZ308 glioblastoma cells. These results suggest that, in glioblastoma cells, ET-1, mainly acting via the ET(B) receptor, is a survival/antiapoptotic factor produced by tumor vasculature, but not a proliferation factor, involving protein kinase C and extracellular signal-regulated kinase pathways, and stabilization of the short form of FLIP.
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PMID:The endothelin system in human glioblastoma. 1109 28

The steps required for new vessel growth are biologically complex and require coordinate regulation of contributing components, including modifications of cell--cell interactions, proliferation and migration of endothelial cells and matrix degradation. The observation that in vivo angiogenesis is accompanied by vasodilation, that many angiogenesis effectors possess vasodilating properties and that tumor vasculature is in a persistent state of vasodilation, support the existence of a molecular/biochemical link between vasodilation and angiogenesis. Several pieces of evidence converge in the indication of a role for nitric oxide (NO), the factor responsible for vasodilation, in physiological and pathological angiogenesis. Data originated in different labs indicate that NO can act both as an 'actor' of angiogenesis and as a 'director of angiogenesis', both functions being equally expressed during physiological and pathological processes. NO significantly contributes to the prosurvival/proangiogenic program of capillary endothelium by triggering and transducing cell growth and differentiation via endothelial-constitutive NO synthase (ec-NOS) activation, cyclic GMP (cGMP) elevation, mitogen activated kinase (MAPK) activation and fibroblast growth factor-2 (FGF-2) expression. Re-establishment of a balanced NO production in the central nervous system results in a reduction of cell damage during inflammatory and vascular diseases. Elevation of NOS activity in correlation with angiogenesis and tumor progression has been extensively reported in experimental and human tumors. In the brain, tumor expansion and edema formation are sensitive to NOS inhibition. On this basis, the nitric oxide pathway appears to be a promising target for consideration in pro- and anti-angiogenic therapeutic strategies. The use of NOS inhibitors seems appropriate to reduce edema, block angiogenesis and facilitate antitumor drug delivery.
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PMID:Nitric oxide and angiogenesis. 1124 73

Abundant data now demonstrate that the growth of new blood vessels, termed angiogenesis, plays both pathological and beneficial roles in human disease. Based on these data, a tremendous effort has been undertaken to understand the molecular mechanisms that drive blood vessel growth in adult tissues. Tie2 recently was identified as a receptor tyrosine kinase expressed principally on vascular endothelium. Disrupting Tie2 function in mice resulted in embryonic lethality with defects in embryonic vasculature, suggesting a role in blood vessel maturation and maintenance. Based on these studies, we undertook a series of studies to probe the function of Tie2 in adult vasculature that will form the focus of this chapter. Consistent with a role in blood vessel growth in adult vasculature, Tie2 was upregulated and activated in the endothelium of rat ovary and in healing rat skin wounds, both areas of active angiogenesis. Moreover, Tie2 was upregulated in the endothelium of vascular "hot spots" in human breast cancer specimens. Surprisingly, Tie2 also was expressed and activated in the endothelium of all normal rat tissues examined, suggesting a role in maintenance of adult vasculature. To determine the functional role of Tie2 in tumor vasculature, a soluble Tie2 extracellular domain (ExTek) was designed that blocked the activation of Tie2 by its activating ligand, angiopoietin 1 (Ang1). Administration of recombinant ExTek protein or an ExTek adenovirus inhibited tumor growth and metastasis in rodent tumor models, demonstrating a functional role for Tie2 in pathological angiogenesis in adult tissues. To begin to understand the endothelial signaling pathways and cellular responses that mediate Tie2 function, we identified signaling molecules that are recruited to the activated, autophosphorylated Tie2 kinase domain. Two of these molecules, SHP2 and GRB2, are part of the pathway upstream of mitogen-activated protein kinase (MAPK) activation, a pathway that may be responsible for morphogenetic effects of Tie2 on endothelial cells. Another signaling molecule, p85, is responsible for recruitment of phosphatidylinositol 3 kinase (PI3-K) and activation of the Akt/PI3-K pathway. Akt/PI3-K has emerged as a critical pathway downstream of Tie2 that is necessary for cell survival effects as well as for chemotaxis, activation of endothelial nitric oxide synthase, and perhaps for anti-inflammatory effects of Tie2 activation. Taken together, these studies and many others demonstrate that the Tie2 pathway has important functions in adult tissues, in both quiescent vasculature and during angiogenesis, and help to validate the Tie2 pathway as a therapeutic target.
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PMID:Functional significance of Tie2 signaling in the adult vasculature. 1474 97

Therapeutic radiation is widely used in cancer treatments. The success of radiation therapy depends not only on the radiosensitivity of tumor cells but also on the radiosensitivity of endothelial cells lining the tumor vasculature. Vascular endothelial growth factor (VEGF) plays a critical role in protecting endothelial cells against a number of antitumor agents including ionizing radiation. Strategies designed to overcome the survival advantage afforded to endothelial cells by VEGF might aid in enhancing the efficacy of radiation therapy. In this report we examined the signaling cascade(s) involved in VEGF-mediated protection of endothelial cells against gamma-irradiation. gamma-Irradiation-induced apoptosis of human dermal microvascular endothelial cells (HDMECs) was predominantly mediated through the p38 MAPK pathway as an inhibitor of p38 MAPK (PD169316), and dominant negative mutants of p38 MAPK could significantly enhance HDMEC survival against gamma-irradiation. Inhibition of the PI3K and MAPK pathways markedly up-regulated gamma-irradiation-mediated p38 MAPK activation resulting in enhanced HDMEC apoptosis. In contrast, VEGF-treated HDMECs were protected from gamma-irradiation-induced apoptosis predominantly through the PI3K/Akt pathway. Bcl-2 expression was markedly elevated in VEGF-treated HDMECs, and it was significantly inhibited by the PI3K inhibitor LY294002. HDMECs exposed to irradiation showed a significant decrease in Bcl-2 expression. In contrast, VEGF-stimulated HDMECs, when irradiated, maintained higher levels of Bcl-2 expression. Taken together our results suggest that gamma-irradiation induces endothelial cell apoptosis predominantly via the activation of p38 MAPK, and VEGF protects endothelial cells against gamma-irradiation predominantly via the PI3K-Akt-Bcl-2 signaling pathway.
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PMID:p38 MAPK mediates gamma-irradiation-induced endothelial cell apoptosis, and vascular endothelial growth factor protects endothelial cells through the phosphoinositide 3-kinase-Akt-Bcl-2 pathway. 1529 52

Inhibition of ERK-MAPK signaling by expression of dominant-negative MEK1 in the tumor vasculature suppresses angiogenesis and tumor growth. In an organotypic tissue culture angiogenesis assay, ERK-MAPK inhibition during the migratory phase results in loss of bipolarity, detachment, and cell death of isolated endothelial cells and retraction of sprouting tubules. These effects are the consequence of upregulated Rho-kinase signaling. Transient inhibition of Rho-kinase rescues the effects of ERK-MAPK inhibition in vitro and in vivo, promotes sprouting, and increases vessel length in tumors. We propose a regulatory role of Rho-kinase by ERK-MAPK during angiogenesis that acts through the control of actomyosin contractility. Our data delineate a mechanism by which ERK-MAPK promotes endothelial cell survival and sprouting by downregulating Rho-kinase signaling.
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PMID:ERK-MAPK signaling opposes Rho-kinase to promote endothelial cell survival and sprouting during angiogenesis. 1641 70

Epidermal growth factor (EGF) receptor family members are expressed by tumor cells and contribute to tumor progression. The expression and activity of EGF receptors in endothelial cells are less well characterized. Analysis of tumor-derived endothelial cells showed that they express EGFR, ErbB2, and ErbB4, whereas their normal counterparts express ErbB2, ErbB3, and ErbB4. The gain in expression of EGFR and the loss of ErbB3 expression in tumor vasculature was also observed in vivo. As a consequence of their expressing EGFR, tumor endothelial cells responded to EGF and other EGF family members by activating both EGFR and ErbB2, by activating the downstream mitogen-activated protein kinase pathway, and by enhanced proliferation. On the other hand, normal endothelial cells did not respond to EGF but instead were responsive to neuregulin (NRG), a ligand for ErbB3 and ErbB4. NRG activated ErbB3 in normal endothelial cells and inhibited growth of these cells. In contrast, tumor endothelial cells, which do not express ErbB3, were not growth inhibited by NRG. Furthermore, due to their expression of EGFR, tumor endothelial cells, unlike normal endothelial cells, are direct targets for EGFR kinase inhibitors. These low-molecular-weight compounds block EGF-induced EGFR activation and proliferation of tumor endothelial cells. These results suggest that a gain of EGF-induced endothelial cell proliferation, and loss of NRG-induced growth inhibition in tumor endothelial cells constitutes a switch that promotes tumor angiogenesis. In addition, these results suggest that EGFR kinase inhibitors may be effective for antiangiogenesis therapy by specifically targeting the tumor, but not the normal, vasculature.
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PMID:Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. 1648 18

Vascular disrupting agents (VDAs) represent a novel approach to the treatment of cancer, resulting in the collapse of tumor vasculature and tumor death. 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a VDA currently in advanced phase II clinical trials, yet its precise mechanism of action is unknown despite extensive preclinical and clinical investigations. Our data demonstrate that DMXAA is a novel and specific activator of the TANK-binding kinase 1 (TBK1)-interferon (IFN) regulatory factor 3 (IRF-3) signaling pathway. DMXAA treatment of primary mouse macrophages resulted in robust IRF-3 activation and approximately 750-fold increase in IFN-beta mRNA, and in contrast to the potent Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS), signaling was independent of mitogen-activated protein kinase (MAPK) activation and elicited minimal nuclear factor kappaB-dependent gene expression. DMXAA-induced signaling was critically dependent on the IRF-3 kinase, TBK1, and IRF-3 but was myeloid differentiation factor 88-, Toll-interleukin 1 receptor domain-containing adaptor inducing IFN-beta-, IFN promoter-stimulator 1-, and inhibitor of kappaB kinase-independent, thus excluding all known TLRs and cytosolic helicase receptors. DMXAA pretreatment of mouse macrophages induced a state of tolerance to LPS and vice versa. In contrast to LPS stimulation, DMXAA-induced IRF-3 dimerization and IFN-beta expression were inhibited by salicylic acid. These findings detail a novel pathway for TBK1-mediated IRF-3 activation and provide new insights into the mechanism of this new class of chemotherapeutic drugs.
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PMID:The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis. 1756 15

Anthrax lethal toxin (LT), a virulence factor secreted by Bacillus anthracis, is selectively toxic to human melanomas with the BRAF V600E activating mutation because of its proteolytic activities toward the mitogen-activated protein kinase kinases (MEKs). To develop LT variants with lower in vivo toxicity and high tumor specificity, and therefore greater potential for clinical use, we generated a mutated LT that requires activation by matrix metalloproteinases (MMPs). This engineered toxin was less toxic than wild-type LT to mice because of the limited expression of MMPs by normal cells. Moreover, the systemically administered toxin produced greater anti-tumor effects than wild-type LT toward human xenografted tumors. This was shown to result from its greater bioavailability, a consequence of the limited uptake and clearance of the modified toxin by normal cells. Furthermore, the MMP-activated LT had very potent anti-tumor activity not only to human melanomas containing the BRAF mutation but also to other tumor types, including lung and colon carcinomas regardless of their BRAF status. Tumor histology and in vivo angiogenesis assays showed that this anti-tumor activity is due largely to the indirect targeting of tumor vasculature and angiogenic processes. Thus, even tumors genetically deficient in anthrax toxin receptors were still susceptible to the toxin therapy in vivo. Moreover, the modified toxin also displayed lower immunogenicity compared with the wild-type toxin. All these properties suggest that this MMP-activated anti-tumor toxin has potential for use in cancer therapy.
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PMID:Matrix metalloproteinase-activated anthrax lethal toxin demonstrates high potency in targeting tumor vasculature. 1797 67

The mitogen-activated protein kinase (MAPK) signaling pathways play essential roles in cell proliferation and differentiation. Recent studies also show the activation of MAPK signaling pathways in tumorigenesis, metastasis, and angiogenesis of multiple human malignancies, including renal cell carcinoma (RCC). To assess the role of this pathway in regulating the proliferation and survival of RCC cells, we first examined the expression of MAPK kinase (MKK) and MAPK in clear cell RCC and confirmed the overexpression of MKK1 and extracellular signal-regulated kinase 2 (ERK2) in these tumors. We then tested the effects of pharmacologic inhibition of MKK on human RCC cell lines, both in vitro and in vivo, using anthrax lethal toxin (LeTx), which cleaves and inactivates several MKKs. Western blotting showed that the phosphorylation levels of ERK, c-Jun-NH(2) kinase, and p38 MAPK decreased after 72 h of LeTx treatment. Exposure to LeTx for 72 h reduced cell proliferation by 20% without significant effects on cell cycle distribution and apoptosis. Anchorage-independent growth of RCC cells was dramatically inhibited by LeTx. In vivo studies showed that tumor growth of RCC xenografts could be suppressed by LeTx. Extensive necrosis and decreased tumor neovascularization were observed after LeTx treatment. LeTx also showed direct inhibition of proliferation of endothelial cells in vitro. Our results suggest that suppression of one or more MAPK signaling pathways may inhibit RCC growth through the disruption of tumor vasculature.
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PMID:Inhibition of MAPK kinase signaling pathways suppressed renal cell carcinoma growth and angiogenesis in vivo. 1817 99


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