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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular details of hypoxia-induced cellular responses have been difficult to identify since there is as yet no known oxygen receptor. We used cDNA microarray technology to extend our studies pertaining to these molecular details in human hepatocellular carcinoma (Hep3B) cells that produce erythropoietin (Epo) in response to hypoxia. Of approximately 1200 genes in the array, those associated with integrin-linked kinase (ILK), fibronectin precursor and glycogen synthase kinase-3beta (GSK-3beta) were markedly stimulated after exposure of Hep3B cells to low oxygen (1%) for 6 h. Epo, HIF-1, and von Hippel-Lindau cDNAs were measured in parallel as markers of low oxygen responses in Hep3B cells. ILK is a serine, threonine protein kinase that interacts with the cytoplasmic domains of integrin beta1 and beta3. This interaction localizes ILK to focal adhesion plaques. ILK is stimulated by cell-fibronectin interaction as well as insulin. It is regulated in a phosphatidylinositol 3-kinase dependent manner and can phosphorylate protein kinase B (PKB/AKT) and GSK-3beta. As a result of these and other activities ILK has been shown to affect anchorage-independent cell survival, cell cycle progression and tumorigenesis in nude mice. ILK has also been implicated in the Wnt pathway and as a critical target in PTEN-dependent tumor therapies. To our knowledge this is the first report implicating the ILK pathway in low oxygen responses. Other genes identified as a result of the microarray analysis not previously known to change as a result of low oxygen treatment were elongation factor-1alpha, glycyl-tRNA synthetase, and laminin receptor protein-1. These findings were all corroborated by RT-PCR assays and in some instances Western blot analysis.
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PMID:Gene microarray analysis reveals a novel hypoxia signal transduction pathway in human hepatocellular carcinoma cells. 1140 33

The serine/threonine kinase Akt/PKB and the oxygen-responsive transcription factor HIF-1 share the ability to induce such processes as angiogenesis, glucose uptake, and glycolysis. Akt activity and HIF-1 are both essential for development and implicated in tumor growth. Upon activation by products of phosphatidylinositol 3-kinase (PI3K), Akt phosphorylates downstream targets that stimulate growth and inhibit apoptosis. Previous reports suggest that Akt may achieve its effects on angiogenesis and glucose metabolism by stimulating HIF-1 activity. We report here that, whereas serum stimulation can induce a slight accumulation of HIF-1 alpha protein in a PI3K/Akt pathway-dependent fashion, hypoxia induces much higher levels of HIF-1 alpha protein and HIF-1 DNA binding activity independently of PI3K and mTOR activity. In addition, we find the effects of constitutively active Akt on HIF-1 activity are cell-type specific. High levels of Akt signaling can modestly increase HIF-1 alpha protein, but this increase does not affect HIF-1 target gene expression. Therefore, the PI3K/Akt pathway is not necessary for hypoxic induction of HIF-1 subunits or activity, and constitutively active Akt is not itself sufficient to induce HIF-1 activity.
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PMID:Phosphatidylinositol 3-kinase/Akt signaling is neither required for hypoxic stabilization of HIF-1 alpha nor sufficient for HIF-1-dependent target gene transcription. 1185 74

This article discusses the role of transcription factors in vascular endothelial growth factor (VEGF) gene expression. Angiogenesis is a complex and multilevel process of new capillary formation on the basis of already existing blood vessels. Physiologically, it is a very strictly regulated process, which results in a balance between stimulatory (angiogenic) and inhibitory (angiostatic) factors to control the correct development of blood vessels. There are many very well characterized angiogenic and angiostatic factors that can modulate VEGF expression. Some of them (e.g. HIF-1, AP-1, and Sp-1) are transcription factors, proteins that bind to the VEGF promoter to initiate and activate the transcription of a gene directly. Others, like nitric oxide or cytokines, are agents that stimulate the transcription factors through different cellular signaling pathways. There are also oncogenes (V-SRC, bcl-2) and tumor suppressor genes (VHL), the mutations of which lead indirectly to increased transcription of the VEGF gene.
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PMID:Transcription factors having impact on vascular endothelial growth factor (VEGF) gene expression in angiogenesis. 1503 60

Diverse extrinsic and intrinsic cues must be integrated within a developing organism to ensure appropriate growth at the cellular and organismal level. In Drosophila, the insulin receptor/TOR/S6K signaling network plays a fundamental role in the control of metabolism and cell growth. Here we show that scylla and charybdis, two homologous genes identified as growth suppressors in an EP (enhancer/promoter) overexpression screen, act as negative regulators of growth. The simultaneous loss of both genes generates flies that are more susceptible to reduced oxygen concentrations (hypoxia) and that show mild overgrowth phenotypes. Conversely, scylla or charybdis overactivation reduces growth. Growth inhibition is associated with a reduction in S6K but not PKB/Akt activity. Together, genetic and biochemical analysis places Scylla/Charybdis downstream of PKB and upstream of TSC. Furthermore, we show that scylla and charybdis are induced under hypoxic conditions and that scylla is a target of Drosophila HIF-1 (hypoxia-inducible factor-1) like its mammalian counterpart RTP801/REDD1, thus establishing a potential cross-talk between growth and oxygen sensing.
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PMID:The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. 1554 26

Drug resistance is a major obstacle in the development of effective cancer therapy. It was reported that many chemotherapeutic drugs such as vincristine (VCR), a potent anti-tumor agent that associates with microtubules and disrupts the microtubular system, was found in acquisition of drug-resistance associated with an increase of HIF-1 expression via activating the NF-gammaB signal pathway. However, the multifactorial mechanism responsible for VCR increased HIF-1alpha expression remains to be fully elucidated. MGr1-Ag was previously reported by our laboratory as an upregulated protein in VCR-resistant cell lines SGC7901/VCR. In our study, detection of HIF-1 expression in SGC7901 cells and SGC7901/VCR cell or VCR-treated SGC7901cells showed that VCR could induce a significant expression of HIF-1alpha and VCR-resistant SGC7901/VCR cells had much higher expression of HIF-1alpha. Under nonhypoxic condition, VCR could enhance DNA binding activity and transcriptional activity of HIF-1alpha by 5.42- and 9.42-fold, respectively. Further study showed that forced expression of MGr1-Ag/37LRP upregulated HIF-1alpha protein expression and transcriptional activity in gastric cancer cell under nonhypoxic condition whereas siRNA targeting MGr1-Ag showed a markedly decreased VCR-induced HIF-1alpha expression and transcriptional activity (P < 0.05). SiRNA targeting FAK or inhibitors of phosphatidylinositol 3-kinase (PI3K) and MAPK could inhibit VCR-induced HIF-1alpha expression, suggesting FAK-PI3K and p42/44MAPK (Erk1/2) may be the major signaling molecules in MGr1-Ag/37LRP-induced HIF-1alpha expression and activity. These data support a model in which MGr1-Ag was a focal point for the convergence of VCR-mediated signaling events leading to HIF-1Alpha induction, thus revealing a novel aspect of HIF-1alpha regulation.
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PMID:Involvement of MGr1-Ag/37LRP in the vincristine-induced HIF-1 expression in gastric cancer cells. 1747 62

It has been shown that ultrasound (US) stimulation accelerates fracture healing in the animal models and clinical studies. Nitric oxide (NO) is a crucial early mediator in mechanically induced bone formation. Here we found that US stimulation increased NO formation and the protein level of inducible nitric-oxide synthase (iNOS). US-mediated iNOS expression was attenuated by anti-integrin alpha5beta1 or beta1 antibodies but not anti-integrin alphavbeta3 or beta3 antibodies or focal adhesion kinase mutant. Integrin-linked kinase (ILK) inhibitor (KP-392), Akt inhibitor (1L-6-hydroxymethyl-chiro-inositol-2-[(R)-2-O-methyl-3-O-octadecylcarbonate]) or mammalian target of rapamycin (mTOR) inhibitor (rapamycin) also inhibited the potentiating action of US. US stimulation increased the kinase activity of ILK and phosphorylation of Akt and mTOR. Furthermore, US stimulation also increased the stability and activity of HIF-1 protein. The binding of HIF-1alpha to the HRE elements on the iNOS promoter was enhanced by US stimulation. Moreover, the use of pharmacological inhibitors or genetic inhibition revealed that both ILK/Akt and mTOR signaling pathway were potentially required for US-induced HIF-1alpha activation and subsequent iNOS up-regulation. Taken together, our results provide evidence that US stimulation up-regulates iNOS expression in osteoblasts by an HIF-1alpha-dependent mechanism involving the activation of ILK/Akt and mTOR pathways via integrin receptor.
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PMID:Ultrasound induces hypoxia-inducible factor-1 activation and inducible nitric-oxide synthase expression through the integrin/integrin-linked kinase/Akt/mammalian target of rapamycin pathway in osteoblasts. 1758 51

Iron depletion improves insulin resistance in patients with nonalcoholic fatty liver disease and diabetes and also stabilizes the hypoxia-inducible factor (HIF)-1, resulting in increased glucose uptake in vitro. This study investigated the effect of iron depletion by deferoxamine on insulin signaling and glucose uptake in HepG2 hepatocytes and in rat liver. In HepG2 cells, deferoxamine stabilized HIF-1alpha and induced the constitutive glucose transporter Glut1 and the insulin receptor. Up-regulation of insulin receptor by deferoxamine was mimicked by the intracellular iron chelator deferasirox and the hypoxia inducer CoCl2 and required the HIF-1 obligate partner ARNT/HIF-1beta. Iron depletion increased insulin receptor activity, whereas iron supplementation had the opposite effect. Deferoxamine consistently increased the phosphorylation status of Akt/PKB and its targets FoxO1 and Gsk3beta, which mediate the effect of insulin on gluconeogenesis and glycogen synthesis, and up-regulated genes involved in glucose uptake and utilization. Iron depletion of Sprague-Dawley rats increased HIF-1alpha expression, improved glucose clearance, and was associated with up-regulation of insulin receptor and Akt/PKB levels and of glucose transport in hepatic tissue. Conversely, gluconeogenic genes were not affected. In rats with fatty liver because of a high-calorie and high-fat diet, glucose clearance was increased by iron depletion and decreased by iron supplementation. Thus, iron depletion by deferoxamine up-regulates glucose uptake, and increases insulin receptor activity and signaling in hepatocytes in vitro and in vivo.
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PMID:Iron depletion by deferoxamine up-regulates glucose uptake and insulin signaling in hepatoma cells and in rat liver. 1824 13

Hypoxia-inducible factor (HIF-1) plays a central role in the cellular adaptive response to hypoxic conditions, which are closely related to pathophysiological conditions, such as cancer. Although reactive oxygen species (ROS) have been implicated in the regulation of hypoxic and non-hypoxic induction of HIF-1 under various conditions, the role of ROS is quite controversial, and the mechanism underlying the HIF-1 regulation by ROS is not completely understood yet. Here, we investigated the biochemical mechanism for the ROS-induced HIF-1 by revealing a novel role of adenosine monophosphate-activated protein kinase (AMPK) and the upstream signal components. AMPK plays an essential role as energy-sensor under adenosine triphosphate-deprived conditions. Here we report that ROS induced by a direct application of H(2)O(2) and menadione to DU145 human prostate carcinoma resulted in accumulation of HIF-1alpha protein by attenuation of its degradation and activation of its transcriptional activity in an AMPK-dependent manner. By way of contrast, AMPK was required only for the transcriptional activity of HIF-1 under hypoxic condition, revealing a differential role of AMPK in these two stimuli. Furthermore, our data show that inhibition of AMPK enhances HIF-1alpha ubiquitination under ROS condition. Finally, we show that the regulation of HIF-1 by AMPK in response to ROS is under the control of c-Jun N-terminal kinase and Janus kinase 2 pathways. Collectively, our findings identify AMPK as a key determinant of HIF-1 functions in response to ROS and its possible role in the sophisticated HIF-1 regulatory mechanisms.
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PMID:Reactive oxygen species stabilize hypoxia-inducible factor-1 alpha protein and stimulate transcriptional activity via AMP-activated protein kinase in DU145 human prostate cancer cells. 1825 5

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

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


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