Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia-inducible factor-1 (HIF-1) controls the expression of a number of genes such as vascular endothelial growth factor and erythropoietin in low oxygen conditions. However, the molecular mechanisms that underlie the activation of the limiting subunit, HIF-1alpha, are still poorly resolved. Results showing that endogenous HIF-1alpha migrated 12 kDa higher than in vitro translated protein led us to evaluate the possible role of phosphorylation on this phenomenon. We report here that HIF-1alpha is strongly phosphorylated in vivo and that phosphorylation is responsible for the marked differences in the migration pattern of HIF-1alpha. In vitro, HIF-1alpha is phosphorylated by p42 and p44 mitogen-activated protein kinases (MAPKs) and not by p38 MAPK or c-Jun N-terminal kinase. Interestingly, p42/p44 MAPK stoichiometrically phosphorylate HIF-1alpha in vitro, as judged by a complete upper shift of HIF-1alpha. More importantly, we demonstrate that activation of the p42/p44 MAPK pathway in quiescent cells induced the phosphorylation and shift of HIF-1alpha, which was abrogated in presence of the MEK inhibitor, PD 98059. Finally, we found that in a vascular endothelial growth factor promoter mutated at sites previously shown to be MAPK-sensitive (SP1/AP2-88-66 site), p42/p44 MAPK activation is sufficient to promote the transcriptional activity of HIF-1. This interaction between HIF-1alpha and p42/p44 MAPK suggests a cooperation between hypoxic and growth factor signals that ultimately leads to the increase in HIF-1-mediated gene expression.
 ...
PMID:p42/p44 mitogen-activated protein kinases phosphorylate hypoxia-inducible factor 1alpha (HIF-1alpha) and enhance the transcriptional activity of HIF-1. 1055 17

Under low oxygen tension, cells increase the transcription of specific genes that are involved in angiogenesis, erythropoiesis, and glycolysis. Hypoxia-induced gene expression primarily depends on the stabilization of the alpha-subunit of hypoxia-inducible factor-1 (HIF-1alpha), which acts as a heterodimeric trans-activator. Our results indicate that stabilization of HIF-1alpha protein by treatment of proteasome inhibitors, is not sufficient for hypoxia-induced gene activation, and an additional hypoxia-dependent modification is necessary for gene expression by HIF-1alpha. Here, we demonstrate that mitogen-activated protein kinase kinase-1 (MEK-1) inhibitor PD98059 does not change either the stabilization or DNA binding ability of HIF-1alpha but it inhibits the trans-activation ability of HIF-1alpha, thereby it reduces the hypoxia-induced transcription of both an endogenous target gene and a hypoxia-responsive reporter gene. We found that hypoxia induced p42/p44 mitogen-activated protein kinases (MAPKs) that are target protein kinases of MEK-1, and that expression of dominant-negative p42 and p44 MAPK mutants reduced HIF-1-dependent transcription of the hypoxia-responsive reporter gene. Our results are the first to identify that hypoxia-induced trans-activation ability of HIF-1alpha is regulated by different mechanisms than its stabilization and DNA binding, and that these processes can be experimentally dissociated. MEK-1/p42/p44 MAPK regulates the trans-activation, but not the stabilization or DNA binding ability, of HIF-1alpha.
 ...
PMID:Mitogen-activated protein kinase kinase inhibitor PD98059 blocks the trans-activation but not the stabilization or DNA binding ability of hypoxia-inducible factor-1alpha. 1130 6

The damage caused to mammalian neurons during ischaemic events in the brain (e.g. following a stroke), is an area of major interest to neuroscientists. The neurons of hypoxia-tolerant vertebrates offer unique models for identifying new strategies to enhance the survival of hypoxia-vulnerable neurons. In this review, we describe recent advances in our understanding of how hypoxia-tolerant neurons detect decreases in oxygen and create signals that have immediate and long-term effects on cell function and survival. Sensing and adapting to low oxygen tension involves numerous modalities with different times of activation and effect. Sensors include membrane proteins such as ionotropic ion channels, membrane or cytosolic heme proteins, mitochondrial proteins and/or oxygen sensitive transcription factors such as HIF-1alpha and NFkappaB. Signaling molecules involved in O(2) sensing include mitogen-activated protein kinases, ions such as Ca(2+) and metabolites such as adenosine. These signals act rapidly to reduce the conductance of ion channels (ion flux arrest) and production of energy (metabolic arrest), and slowly to activate specific genes. The ability to construct an energy budget, illustrating which physiological processes are depressed during both long-term and acute metabolic suppression in hypoxia-tolerant neurons, would be of significant value in devising new strategies for neuroprotection. Additionally it is not known how metabolism is regulated at 'pilot-light' levels at which energy-producing and energy-consuming processes are balanced. The regulation of organelle and cell fate during long-term hypoxia is almost completely unexplored, and whether programmed cell death and regeneration of lost neurons occur following protracted dormancy is also of considerable interest.
 ...
PMID:Adaptive responses of vertebrate neurons to hypoxia. 1240 84

In the last few decades it has become clear that detailed understanding of the mechanisms of angiogenesis, a process leading to growth of new blood vessels, should lead to improved treatment of diseases such as ischemic disorders and cancer where neovascularization is impaired or activated, respectively. In this review, we will outline some of our recent findings concerning the regulation of the vascular endothelial growth factor (VEGF), a key player in angiogenesis and one of its transcription factors, the hypoxia-inducible factor-1 (HIF-1) a master gene product driving adaptation to hypoxia. We will discuss the observation that growth factors and oncogenic transformation via the mitogen-activated protein kinases p42/p44 MAPKs not only activate the VEGF promoter through the Sp1/AP-2 transcriptional factor complex but also phosphorylate HIF-1alpha leading in turn to enhance HIF-1 dependent transcriptional activation of VEGF. The stress-activated protein kinases (SAPK) also contribute to angiogenesis by stabilizing VEGF mRNA. Finally, we will present recent advances into oxygen-sensing, in particular the HIF-hydroxylases that govern HIF-1alpha instability (PHD2) or inactivation (FIH-1). The revelation of these oxygen sensors has provided pharmacologists with new molecular targets for the development of novel therapies to control angiogenesis either positively or negatively.
 ...
PMID:Protein kinases and the hypoxia-inducible factor-1, two switches in angiogenesis. 1257 Aug 1

Hypoxia-inducible factor-1 (HIF-1), which is present at higher levels in human tumors, plays important roles in tumor promotion. It is composed of HIF-1alpha and HIF-1beta subunits and its activity depends on the amount of HIF-1alpha, which is tightly controlled by cellular oxygen tension. In addition to hypoxia, various nonhypoxic stimuli can stabilize HIF-1alpha in tumor cells, implying that both hypoxic and nonhypoxic stimuli contribute to the overexpression of HIF-1alpha in tumors. On the other hand, phorbol esters such as phorbol-12-myristate-13-acetate (PMA) are known to be potent tumor promoters. Here, we identified a novel HIF-1alpha isoform, which is regulated primarily by PMA. The variant mRNA lacks exon 11 and produces a 785-amino acid isoform (HIF-1alpha(785)) without altering the reading frame and therefore the COOH-terminal transcriptional activity. HIF-1alpha(785) is induced markedly by PMA and heat shock, the latter of which is also known to induce HIF-1alpha. HIF-1alpha(785) escapes from lysine acetylation because of the loss of Lys(532) and was stabilized under normoxic conditions. Its expression was blocked by reducing agents and by a mitogen-activated protein/extracellular signal-regulated kinase-1 inhibitor and enhanced by hydrogen peroxide. In addition, HIF-1alpha(785) overexpression strikingly enhanced tumor growth in vivo. These results suggest that HIF-1alpha(785) is induced by PMA under normoxic conditions via a redox-dependent mitogen-activated protein/extracellular signal-regulated kinase-1 pathway and that it plays an important role in tumor promotion.
 ...
PMID:Phorbol ester stimulates the nonhypoxic induction of a novel hypoxia-inducible factor 1alpha isoform: implications for tumor promotion. 1469 84

Both type 1 and type 2 diabetes can lead to altered retinal microvascular function and diabetic retinopathy. Insulin signaling may also play a role in this process, and mice lacking insulin receptors in endothelial cells are protected from retinal neovascularization. To define the role of diabetes in retinal function, we compared insulin signaling in the retinal vasculature of mouse models of type 1 (streptozotocin) and type 2 diabetes (ob/ob). In streptozotocin mice, in both retina and liver, insulin receptor (IR) and insulin receptor substrate (IRS)-2 protein and tyrosine phosphorylation were increased by insulin, while IRS-1 protein and its phosphorylation were maintained. By contrast, in ob/ob mice, there was marked down-regulation of IR, IRS-1, and IRS-2 protein and phosphorylation in liver; these were maintained or increased in retina. In both mice, Phosphatidylinositol 3,4,5-trisphosphate generation by acute insulin stimulation was enhanced in retinal endothelial cells. On the other hand, protein levels and phosphorylation of PDK1 and Akt were decreased in retina of both mice. Interestingly, phosphorylation of p38 mitogen-activated protein kinase and ERK1 were responsive to insulin in retina of both mice but were unresponsive in liver. HIF-1alpha and vascular endothelial growth factor were increased and endothelial nitric-oxide synthase was decreased in retina. These observations indicate that, in both insulin-resistant and insulin-deficient diabetic states, there are alterations in insulin signaling, such as impaired PDK/Akt responses and enhanced mitogen-activated protein kinases responses that could contribute to the retinopathy. Furthermore, insulin signaling in retinal endothelial cells is differentially altered in diabetes and is also differentially regulated from insulin signaling in classical target tissues such as liver.
 ...
PMID:Altered insulin signaling in retinal tissue in diabetic states. 1520 Dec 86

Angiotensin II (ANG II) induces cell-cycle arrest of cultured proximal tubular cells, resulting in cellular hypertrophy. This ANG II-mediated hypertrophy is associated with the induction of p27(Kip1), an inhibitor of G1 phase cyclin-dependent kinase cyclin complexes. We have recently demonstrated that ANG II-mediated expression of p27(Kip1) and induction of cellular hypertrophy depend on the generation of reactive oxygen species (ROS). The effects of ROS are mediated by stimulation of mitogen-activated protein (MAP) kinases. p44/42 MAP kinase directly phosphorylates p27(Kip1) at serine-threonine residues and increases thereby its half-life time. AT2-receptor activation has been implicated in apoptosis and/or cell differentiation. Recent studies, however, revealed a more indirect role of hypoxia in the antiproliferative effects of ANG II transduced through AT2 receptors. We found that SM-20 is down-regulated in ANG II-stimulated PC12 cells that express only AT2 receptors. It turned out that SM20 is the rat homologue of a dioxygenase that regulates hypoxia-inducible factor 1 (HIF-1). ANG II induces HIF-1alpha by a posttranscriptional mechanism suggesting that SM20 down-regulation leads to stabilization of HIF-1. Thus, ANG II-induced ROS generation plays a pivotal role in several pathophysiological situations, leading to renal growth regulation and remodeling after injury.
 ...
PMID:Role of reactive oxygen species in angiotensin II-mediated renal growth, differentiation, and apoptosis. 1611 39

Hypoxia-inducible factor-1 (HIF-1) is a key regulator of genes crucial to many aspects of cancer biology. The purine nucleoside, adenosine, accumulates within many tissues under hypoxic conditions, including that of tumors. Because the levels of both HIF-1 and adenosine are elevated within the hypoxic environment of solid tumors, we investigated whether adenosine may regulate HIF-1. Here we show that, under hypoxic conditions (< 2% O2), adenosine upregulates HIF-1alpha protein expression in a dose-dependent and time-dependent manner, exclusively through the A3 receptor subtype. The response to adenosine was generated at the cell surface because the inhibition of A3 receptor expression, by using small interfering RNA, abolished nucleoside effects. A3 receptor stimulation in hypoxia also increases angiopoietin-2 (Ang-2) protein accumulation through the induction of HIF-1alpha. In particular, we found that A3 receptor stimulation activates p44/p42 and p38 mitogen-activated protein kinases, which are required for A3-induced increase of HIF-1alpha and Ang-2. Collectively, these results suggest a cooperation between hypoxic and adenosine signals that ultimately may lead to the increase in HIF-1-mediated effects in cancer cells.
 ...
PMID:A3 adenosine receptors modulate hypoxia-inducible factor-1alpha expression in human A375 melanoma cells. 1624 72

Vascular endothelial growth factor (VEGF) is the most potent stimulatory factor of angiogenesis. Its expression is induced by reactive oxygen species (ROS) in hypoxic conditions and by insulin in normoxic cells. Both ROS and insulin can activate mitogen-activated protein kinases (MAPKs) and induce the transcriptional factor Sp1, components that are essential for VEGF gene expression. The aim of this study was to investigate the role of ROS producing NADPH oxidase enzymes (NOX-es) in insulin-regulated VEGF gene activation. To achieve this goal we chose HepG2 cells as our model system as these cells express the NADPH oxidase isoform NOX3 and respond to insulin stimulation with enhanced ROS production and mRNA transcription and production of VEGF. We demonstrate that in control cells insulin stimulation leads to H2O2 generation, a biphasic activation of p42/44 MAPK and the induction of both Sp1 and HIF-1alpha. Transfection of NOX3-specific siRNA abrogates H2O2 production and inhibits exclusively the second phase of p42/44 MAPK phosphorylation and Sp1 DNA binding and thus prevents upregulation of VEGF-A mRNA expression. In conclusion, our results demonstrate that NOX3, a ROS generating NADPH oxidase, plays an integral role in insulin-induced p42/44 MAPK signal transmission and VEGF-A production.
 ...
PMID:Insulin-induced vascular endothelial growth factor expression is mediated by the NADPH oxidase NOX3. 1694 73

Enhanced levels of plasminogen activator inhibitor-1 (PAI-1) are considered to be a risk factor for pathological conditions associated with hypoxia or hyperinsulinemia. The expression of the PAI-1 gene is increased by insulin in different cells, although, the molecular mechanisms behind insulin-induced PAI-1 expression are not fully known yet. Here, we show that insulin upregulates human PAI-1 gene expression and promoter activity in HepG2 cells and that mutation of the hypoxia-responsive element (HRE)-binding hypoxia-inducible factor-1 (HIF-1) abolished the insulin effects. Mutation of E-boxes E4 and E5 abolished the insulin-dependent activation of the PAI-1 promoter only under normoxia, but did not affect it under hypoxia. Furthermore, the insulin effect was associated with activation of HIF-1alpha via mitogen-activated protein kinases (MAPKs) but not PDK1 and PKB in HepG2 cells. Furthermore, mutation of a putative FoxO1 binding site which was supposed to be involved in insulin-dependent PAI-1 gene expression influenced the insulin-dependent activation only under normoxia. Thus, insulin-dependent PAI-1 gene expression might be regulated by the action of both HIF-1 and FoxO1 transcription factors.
 ...
PMID:The MAPK pathway and HIF-1 are involved in the induction of the human PAI-1 gene expression by insulin in the human hepatoma cell line HepG2. 1738 80


1 2 Next >>