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)

20-HETE increases the expression of VEGF in human dermal microvascular endothelial cells (ECs). Since VEGF is regulated by hypoxia inducible factor (HIF)-1, we studied whether 20-HETE also upregulates HIF-1alpha using the stable 20-HETE analog 20-hydroxyeicosa-5(Z),14(Z)dienoic acid (WIT003; 1-10 microM) and found that it induced a marked increase in HIF-1alpha protein levels. The increases in VEGF after the addition of WIT003 preceded the changes in HIF-1alpha, and the increases in HIF-1alpha were prevented by a VEGF neutralizing antibody. This suggests that 20-HETE first causes increases in VEGF, which then, in turn, cause the upregulation of HIF-1alpha. Stimulation with exogenously added VEGF also led to an upregulation of HIF-1alpha. Incubation with the MEK1/ERK1/2 inhibitor U-0126 (10 microM) completely abolished the increases in VEGF and thus HIF-1alpha, suggesting the involvement of ERK1/2 activation. The addition of WIT003 resulted in a rapid and sustained increase in superoxide formation. When WIT003 was added in the presence of the nitric oxide (NO) synthase (NOS) inhibitor N-nitro-L-arginine, no changes in superoxide, VEGF, or HIF-1alpha were observed. This suggests that NOS is responsible for the early changes in superoxide induced by WIT003. Furthermore, WIT003 induced the expression of the NADPH oxidase subunit p47(phox) in ECs before the increases in HIF-1alpha. Incubation with polyethylene glycol-superoxide dismutase (400 U/ml), apocynin (100 microM), diphenylene iodonium (10 microM), or p47(phox) downregulation with small interfering (si)RNA all inhibited the increases in HIF-1alpha expression. This indicates that the early changes in superoxide lead to VEGF increases and thereby NADPH oxidase-dependent superoxide production, which is required for HIF-1alpha upregulation. We also found that the higher HIF-1alpha expression induced by WIT003 was accompanied by higher expression of erythropoietin receptor and angiopoietin-2 proteins. These increases were caused by HIF-1alpha because their levels were markedly decreased by siRNA downregulation of HIF-1alpha. 20-HETE may be a novel nonhypoxic regulator of HIF-1alpha and HIF-1alpha-regulated genes in ECs.
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PMID:20-HETE can act as a nonhypoxic regulator of HIF-1alpha in human microvascular endothelial cells. 1950 54

The E3 ubiquitin ligase Siah2 has been implicated in the regulation of the hypoxia response, as well as in the control of Ras, JNK/p38/NF-kappaB signaling pathways. Both Ras/mitogen-activated protein kinase (MAPK) and hypoxia pathways are important for melanoma development and progression, pointing to the possible use of Siah2 as target for treatment of this tumor type. In the present study, we have established a high-throughput electro-chemiluninescent-based assay in order to screen and identify inhibitors of Siah2 ubiquitin ligase activity. Of 1840 compounds screened, we identified and characterized menadione (MEN) as a specific inhibitor of Siah2 ligase activity. MEN attenuated Siah2 self-ubiquitination, and increased expression of its substrates PHD3 and Sprouty2, with concomitant decrease in levels of HIF-1alpha and pERK, the respective downstream effectors. MEN treatment no longer affected PHD3 or Sprouty2 in Siah-KO cells, pointing to its Siah-dependent effects. Further, MEN inhibition of Siah2 was not attenuated by free radical scavenger, suggesting it is ROS-independent. Significantly, growth of xenograft melanoma tumors was inhibited following the administration of MEN or its derivative. These findings reveal an efficient platform for the identification of Siah inhibitors while identifying and characterizing MEN as Siah inhibitor that attenuates hypoxia and MAPK signaling, and inhibits melanoma tumorigenesis.
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PMID:Inhibition of Siah2 ubiquitin ligase by vitamin K3 (menadione) attenuates hypoxia and MAPK signaling and blocks melanoma tumorigenesis. 1971 6

The expression of the potent, constitutively activated EGFR variant, EGFRvIII, has been linked to breast cancer metastasis, but the mechanisms of EGFRvIII and CXCR4 crosstalk, which may facilitate breast cancer invasion, have never been explored. Here we report that CXCR4 expression is increased in breast cancer cells expressing EGFRvIII regardless of the ER/PgR status of the cells. Treatment of EGFRvIII-expressing breast cancer cells with the tyrosine kinase inhibitor, AG1478, reverses CXCR4 expression back to levels expressed in parental cells. In addition, expressing EGFRvIII enhances CXCL12/CXCR4-mediated invasion, which can be inhibited by CXCR4 inhibitors. Surprisingly, CXCR4 mRNA and its transcriptional regulator, HIF-1alpha, are up-regulated only in ER+/PgR+ estrogen-dependent EGFRvIII-expressing breast cancer cells, but not in ER-/PgR- or estrogen-independent cell lines, suggesting that HIF-1alpha and hormone receptor-mediated actions may have a role in the transcriptional regulation of CXCR4. We also demonstrate that p38 MAPK is one of the major down-stream signaling molecules responsible for EGFRvIII/CXCR4-mediated invasion as p38 MAPK activity was induced by CXCL12 stimulation under both normoxic and hypoxic conditions. More interestingly, inhibition of p38 MAPK activity significantly reduced CXCR4 expression and inhibited the invasive potential of EGFRvIII-expressing breast cancer cells, suggesting an essential role for p38 MAPK in EGFRvIII/CXCR4 induced invasion. Furthermore, CXCR4 is regulated post-translationally through decreased expression of AIP4 and beta-arrestin 1/2, molecules involved in CXCR4 internalization, cellular trafficking and degradation. These results provide a plausible mechanism for EGFRvIII-mediated invasion and establish a functional link between EGFRvIII and CXCR4 signaling pathways.
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PMID:EGFR variant-mediated invasion by enhanced CXCR4 expression through transcriptional and post-translational mechanisms. 1983 Jun 94

Microbes regulate a large panel of intracellular signalling events that can promote inflammation and/or enhance tumour progression. Indeed, it has been shown that infection of human intestinal cells with the Afa/Dr diffusely adhering E. coli C1845 strain induces expression of pro-angiogenic and pro-inflammatory genes. Here, we demonstrate that exposure of cryptic-like intestinal epithelial cells to C1845 bacteria induces HIF-1alpha protein levels. This effect depends on the binding of F1845 adhesin to the membrane-associated DAF receptor that initiates signalling cascades promoting translational mechanisms. Indeed, inhibition of MAPK and PI-3K decreases HIF-1alpha protein levels and blocks C1845-induced phosphorylation of the ribosomal S6 protein. Using RNA interference we show that bacteria-induced HIF-1alpha regulates the expression of IL-8, VEGF and Twist1, thereby pointing to a role for HIF-1 in angiogenesis and inflammation. In addition, infection correlates with a loss of E-cadherin and cytokeratin 18 and a rise in fibronectin, suggesting that bacteria may induce an epithelial to mesenchymal transition-like phenotype. Since HIF-1alpha silencing results in reversion of bacteria-induced EMT markers, we speculate that HIF-1alpha plays a key role linking bacterial infection to angiogenesis, inflammation and some aspects of cancer initiation.
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PMID:HIF-1alpha mediates the induction of IL-8 and VEGF expression on infection with Afa/Dr diffusely adhering E. coli and promotes EMT-like behaviour. 2003 80

Tumour hypoxia is associated with increased metastatic potential and resistance to radiotherapy and chemotherapy. Ileal carcinoids are usually metastatic at the time of diagnosis and respond poorly to chemotherapy. The aim of this study was to investigate the extent of hypoxia in ileal carcinoids and the response of tumour cells to induced hypoxia. Vascular endothelial growth factor (VEGF), carbonic anhydrase (CA-IX), hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha were studied by immunohistochemistry in biopsies from 24 patients with ileal carcinoids. All hypoxic markers were shown to be highly expressed in localized areas of the tumours irrespective of tumour location or stage. However, HIF-2alpha expression was significantly higher in distant metastases compared to primary tumours in the same patient. Global gene expression profiling of GOT1 carcinoid cells revealed a marked response to hypoxia. Expression of genes related to epithelial-to-mesenchymal transition and development was altered including increased expression of the C-X-C chemokine receptor type 4 (CXCR4), an important regulator of invasive growth and metastasis formation. High expression of CXCR4 was confirmed by immunohistochemistry in tumour biopsies. Stimulation of GOT1 cells by the CXCR4 ligand, CXCL12 (stromal cell-derived factor 1 (SDF-1)), activated the mitogen-activated protein kinase (MAPK) p42/44 signalling pathway and increased tumour cell migration. We conclude that ileal carcinoids contain hypoxic areas expressing HIF-1alpha, HIF-2alpha and CXCR4. Signalling through the CXCL12-CXCR4 axis may contribute to the metastatic potential of ileal carcinoids. Targeting of HIFs and/or the CXCR4 signalling pathway may offer new therapeutic strategies for carcinoid tumour disease.
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PMID:Hypoxia stimulates CXCR4 signalling in ileal carcinoids. 2007 57

Here we show that the effect of hypoxia on human umbilical cord blood mesenchymal stem cell (hMSC) migration is via the modulation of focal adhesion kinase (FAK) and its related signaling pathways. Hypoxia increased hMSC migration and cell viability, whereas lactate dehydrogenase (LDH) release was not affected for up to 48 h (data not shown). In addition, hypoxia increased the level of reactive oxygen species (ROS) generation in a time-dependent manner. Hypoxia-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and stress-activated protein kinase/c-Jun NH(2)-terminal kinase (SAPK/JNK) were inhibited by the antioxidant (N-acetylcysteine, NAC, 10(-6) M) and (taurine, 4x10(-6) M). Hypoxia-induced endothelial nitric oxide synthase (eNOS) phosphorylation was regulated by p38 MAPK and SAPK/JNK activation. In addition, hypoxia increased the level of hypoxia inducible factor (HIF)-1alpha expression, which was blocked by inhibition of eNOS. Also, hypoxia-induced expression of Flk-1, vascular endothelial growth factor (VEGF), and its secreted form were inhibited by HIF-1alpha small interfering RNA (siRNA). In this hypoxic condition, FAK and Src phosphorylation were increased in a time-dependent manner. Inhibition of Src with specific inhibitor (PP2, 10(-8) M) blocked hypoxia-induced FAK activation. Subsequently, hypoxia-induced FAK phosphorylation was blocked by VEGF siRNA. Finally, hypoxia-induced increase of hMSC migration was inhibited by FAK siRNA. The results indicate that hypoxia increases migration of hMSCs via VEGF-mediated FAK phospholylation and involves the cooperative activity of the ROS, MAPK, eNOS and HIF-1alpha pathways.
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PMID:Role of FAK phosphorylation in hypoxia-induced hMSCS migration: involvement of VEGF as well as MAPKS and eNOS pathways. 2008 32

High exposure of manganese is believed to be a risk factor for respiratory diseases. Evidence suggests that overexpression of HIF-1alpha transcription factor is linked to pulmonary inflammation and vascular change. In this study, we investigated the effect of manganese-chloride (manganese) on expression and activity of HIF-1alpha in various human airway cells, including Hep2 (laryngeal), H292 (bronchial), and A549 (lung). Profoundly, while manganese treatment led to low or little effect on induction of HIF-1alpha protein in H292 or A549 cells, it strongly induced HIF-1alpha protein expression in Hep2 cells. Mn treatment, however, did not induce HIF-1alpha mRNA expression in Hep2 cells. Luciferase experiments further demonstrated that manganese treatment increased the HRE-driven luciferase activity, suggesting that the induced HIF-1 is functional. Interestingly, manganese treatment also caused activation of p38 MAPK, JNK-1/2, ERK-1/2, and ATF-2, but not of PKB or NF-kappaB in Hep2 cells. Importantly, the manganese-mediated expression and activity of HIF-1alpha protein were largely blocked by treatment with the inhibitor of p38 MAPK (SB203580), JNK-1/2 (SP600125), or ERK-1/2 (PD98059), suggesting roles of these MAPKs in the manganese-induced HIF-1alpha protein expression and activity. Moreover, treatment with SP600125 or SB203580, but not PD98059, had partial inhibitory effects on the stability of HIF-1alpha protein induced by manganese, suggesting that p38 MAPK and JNK-1/2 also contribute to the Mn-mediated HIF-1alpha protein stability. These results suggest that manganese is able to up-regulate HIF-1alpha at the protein level in Hep2 cells and the up-regulation is largely dependent of activities of the family of MAPKs.
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PMID:Manganese-mediated up-regulation of HIF-1alpha protein in Hep2 human laryngeal epithelial cells via activation of the family of MAPKs. 2015 96

Hypoxia occurs in a number of pathological states, such as pulmonary, hematological, and cardiovascular disorders. In this study, we examined the molecular mechanism by which hypoxia contributes to increased leukotriene formation. Our studies showed hypoxia augmented the expression of 5-lipoxygenase activating protein (FLAP), a key enzyme in leukotriene formation, in both human pulmonary microvascular endothelial cells and a transformed human brain endothelial cell line. Hypoxia-induced FLAP mRNA expression involved activation of NADPH-oxidase, PI-3 kinase, mitogen-activated protein kinase, NF-kappaB, and hypoxia-inducible factor (HIF)-1alpha. Hypoxia-induced FLAP promoter activity was attenuated on mutation of hypoxia-response elements (HREs) and NF-kappaB binding motif in the FLAP promoter. Hypoxia also augmented binding of HIF-1alpha to HREs in FLAP promoter as demonstrated by EMSA with nuclear extracts. Furthermore, chromain immunoprecipitation analysis showed HIF-1alpha bound to HREs in native chromatin obtained from hypoxia-treated cells. Next, we examined the role of HIF-1alpha regulated microRNAs on FLAP expression. Our studies showed decreased expression of miR-135a and miR-199a-5p in response to hypoxia. However, overexpression of anti-miR-135a and anti-miR-199a-5p oligonucleotides led to a several fold increased FLAP mRNA and protein expression. These studies demonstrate for the first time that hypoxia-mediated FLAP expression is regulated by HREs and NF-kappaB site in its promoter, and negatively regulated by miR-135a and miR-199a-5p, which target the 3'-UTR of FLAP mRNA. An understanding of these regulatory pathways provides new avenues to ameliorate leukotriene formation and hence reactive airway disease, and inflammation in individuals who have sickle cell disease.
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PMID:Hypoxia-mediated expression of 5-lipoxygenase-activating protein involves HIF-1alpha and NF-kappaB and microRNAs 135a and 199a-5p. 2019 22

Insulin-like growth factors (IGFs) stimulate myoblast proliferation and differentiation. It remains elusive how these mutually exclusive cellular responses are elicited by the same growth factor. Here we report that whereas IGF promotes myoblast differentiation under normoxia, it stimulates proliferation under hypoxia. Hypoxia activates the HIF-1 transcriptional program and knockdown of HIF-1alpha changes the mitogenic action of IGF into myogenic action under hypoxia. Conversely, overexpression of HIF-1alpha abolishes the myogenic effect of IGF under normoxia. Under normoxia, IGF activates the Akt-mTOR, p38, and Erk1/2 MAPK pathways. Hypoxia suppresses basal and IGF-induced Akt-mTOR and p38 activity, whereas it enhances and prolongs IGF-induced Erk1/2 activation in a HIF-1-dependent fashion. Activation of Akt-mTOR and p38 promotes myogenesis, and p38 also inhibits proliferation. Activation of Erk stimulates myoblast proliferation but inhibits differentiation. These results suggest that hypoxia converts the myogenic action of IGFs into mitogenic action by differentially regulating multiple signaling pathways via HIF-1-dependent mechanisms. Our findings provide a mechanistic explanation for the paradoxical actions of IGFs during myogenesis and reveal a novel mechanism by which cells sense and integrate growth factor signals and oxygen availability in their microenvironments.
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PMID:Hypoxia converts the myogenic action of insulin-like growth factors into mitogenic action by differentially regulating multiple signaling pathways. 2023 51

The mitochondria are unique cellular organelles that contain their own genome and, in conjunction with the nucleus, are able to transcribe and translate genes encoding components of the electron transport chain (ETC). To do so, the mitochondria must communicate with the nucleus via the production of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2), which are produced as a byproduct of aerobic respiration within the mitochondria. Mitochondrial signaling is proposed to be altered in cancer cells, where the mitochondria are frequently found to harbor mutations within their genome and display altered functional characteristics leading to increased glycolysis. As signaling molecules, ROS oxidize and inhibit MAPK phosphatases resulting in enhanced proliferation and survival, an effect particularly advantageous to cancer cells. In terms of transcriptional regulation, ROS affect the phosphorylation, activation, oxidation, and DNA binding of transcription factors such as AP-1, NF-kappaB, p53, and HIF-1alpha, leading to changes in target gene expression. Increased ROS production by defective cancer cell mitochondria also results in the upregulation of the transcription factor Ets-1, a factor that has been increasingly associated with aggressive cancers.
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PMID:Mechanisms associated with mitochondrial-generated reactive oxygen species in cancer. 2039 86


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