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)

Combined appearance of different cardiovascular risk factors seems to be more prevalent in individuals with decreased insulin sensitivity and increased visceral obesity, thereby being components of the so-called metabolic syndrome or syndrome X. Alterations in the abundance and activity of transcription factors lead to complex dysregulation of gene expression, which might be a key to understand insulin resistance-associated clinical clustering of coronary risk factors at the cellular or gene regulatory level. Recent examples are members of the nuclear hormone receptor superfamily-for example, peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding proteins (SREBPs). Besides their regulation by metabolites and nutrients, these transcription factors are also targets of hormones (like insulin and leptin), growth factors, inflammatory signals, and drugs. Major signaling pathways coupling transcription factors to extracellular stimuli are the MAP kinase cascades. We have recently shown that SREBPs appear to be substrates of MAP kinases and propose that SREBP-1 might play a role in the development of cellular features belonging to lipid toxicity and possibly syndrome X. Thus, the metabolic syndrome appears to be not only a disease or state of altered glucose tolerance, plasma lipid levels, blood pressure, and body fat distribution, but rather a complex clinical phenomenon of dysregulated gene expression.
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PMID:SREBP-1: gene regulatory key to syndrome X? 1207 31

Fetuin inhibits insulin-induced insulin receptor (IR) autophosphorylation and tyrosine kinase activity in vitro, in intact cells, and in vivo. The fetuin gene (AHSG) is located on human chromosome 3q27, recently identified as a susceptibility locus for type 2 diabetes and the metabolic syndrome. Here, we explore insulin signaling, glucose homeostasis, and the effect of a high-fat diet on weight gain, body fat composition, and glucose disposal in mice carrying two null alleles for the gene encoding fetuin, Ahsg (B6, 129-Ahsg(tm1Mbl)). Fetuin knockout (KO) mice demonstrate increased basal and insulin-stimulated phosphorylation of IR and the downstream signaling molecules mitogen-activated protein kinase (MAPK) and Akt in liver and skeletal muscle. Glucose and insulin tolerance tests in fetuin KO mice indicate significantly enhanced glucose clearance and insulin sensitivity. Fetuin KO mice subjected to euglycemic-hyperinsulinemic clamp show augmented sensitivity to insulin, evidenced by increased glucose infusion rate (P = 0.077) and significantly increased skeletal muscle glycogen content (P < 0.05). When fed a high-fat diet, fetuin KO mice are resistant to weight gain, demonstrate significantly decreased body fat, and remain insulin sensitive. These data suggest that fetuin may play a significant role in regulating postprandial glucose disposal, insulin sensitivity, weight gain, and fat accumulation and may be a novel therapeutic target in the treatment of type 2 diabetes, obesity, and other insulin-resistant conditions.
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PMID:Improved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene. 1214 57

The metabolic syndrome in association with obesity is a major clinical problem inducing hypertension, diabetes mellitus, and atherosclerosis. Leptin induces angiogenesis by its proliferative effects on endothelial cells (ECs) via OB receptor (OB-Rb) gene. We evaluated the growth of ECs and intracellular signalings in response to leptin in vitro and the angiogenic effects of leptin in the cornea in vivo with and without adenovirus-mediated transfer of the OB-Rb gene in Zucker fatty (ZF) rats as a model for the metabolic syndrome. Recombinant adenovirus vector encoding rat OB-Rb (Ad.OB-Rb) or Escherichia coli. LacZ (Ad.LacZ) was transfected into cultured ECs from Zucker lean (ZL) rats and ZF rats. Leptin increased DNA synthesis dose-dependently in ECs from ZL rats but not ZF rats. Infection with Ad.OB-Rb, but not with Ad.LacZ, improved the growth effects of leptin in ECs from ZF rats. Leptin induced phosphorylation of Janus kinase (JAK)2, signal transducer and activator of transcription (STAT)3, and extracellular signal-regulated kinase (ERK) in ECs from ZL rats but not ZF rats. Infection with Ad.OB-Rb restored phosphorylation of JAK2 and STAT3 in ECs from ZF rats. Leptin induced angiogenesis in cornea from ZL rats, but not from ZF rats. Coadministration of leptin and Ad.OB-Rb induced angiogenesis in cornea from ZF rats. Ad.LacZ did not influence the angiogenic effects of leptin. The impaired endothelial function with the leptin resistance may be one of causes of the atherosclerosis in the metabolic syndrome.
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PMID:Effects of leptin on endothelial function with OB-Rb gene transfer in Zucker fatty rats. 1292 73

Insulin has a major anabolic function leading to storage of lipidic and glucidic substrates. All its effects result from insulin binding to a specific membrane receptor which is expressed at a high level on the 3 insulin target tissues: liver, adipose tissue and muscles. The insulin receptor exhibits a tyrosine-kinase activity which leads, first, to receptor autophosphorylation and then to tyrosine phosphorylation of substrates proteins, IRS proteins in priority. This leads to the formation of macromolecular complexes close to the receptor. The two main transduction pathways are the phosphatidylinositol 3 kinase pathway activating protein kinase B which is involved in priority in metabolic effects, and the MAP kinase pathway involved in nuclear effects, proliferation and differentiation. However, in most cases, a specific effect of insulin requires the participation of the two pathways in a complex interplay which could explain the pleiotropy and the specificity of the insulin signal. The negative control of the insulin signal can result from hormone degradation or receptor dephosphorylation. However, the major negative control results from phosphorylation of serine/threonine residues on the receptor and/or IRS proteins. This phosphorylation is activated in response to different signals involved in insulin resistance, hyperinsulinism, TNFalpha or increased free fatty acids from adipose tissue, which are transformed inside the cell in acyl-CoA. A deleterious role for molecules issued from the adipose tissue is postulated in the resistance to insulin of the liver and muscles present in type 2 diabetes, obesity and metabolic syndrome.
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PMID:[Insulin signaling: mechanisms altered in insulin resistance]. 1459 14

Insulin resistance and compensatory hyperinsulinemia are recognized not only in type 2 diabetes mellitus(DM) but also in essential hypertension(EHT), hyperlipidemia and obesity; these are known as the components of metabolic syndrome and accumulation of these components increase risk of cardiovascular diseases(CVD). When coronary angiographic findings were evaluated in patients with coronary artery disease(CAD), the severity was higher in CAD with DM than that without DM. Even in CAD without DM, the severity of coronary angiographic findings was higher in CAD with insulin resistance than that without insulin resistance. When residents of rural communities in Japan were followed 8 years, the incidence of CVD was 3.5 times higher in subjects with insulin resistance than those without insulin resistance. One of the intracellular signal transduction of insulin receptor; MAP kinase may be concerned atherosclerotic mechanisms of insulin resistance. These findings suggest that insulin resistance is a significant background of atherosclerosis, and insulin resistance is one of the major facilitation factors of genesis and progression of CVD.
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PMID:[Significance of insulin resistance to atherosclerotic complications in essential hypertension]. 1473 36

Phosphorylation of the cell adhesion protein CEACAM1 increases insulin sensitivity and decreases insulin-dependent mitogenesis in vivo. Here we show that CEACAM1 is a substrate of the EGFR and that upon being phosphorylated, CEACAM1 reduces EGFR-mediated growth of transfected Cos-7 and MCF-7 cells in response to EGF. Using transgenic mice overexpressing a phosphorylation-defective CEACAM1 mutant in liver (L-SACC1), we show that the effect of CEACAM1 on EGF-dependent cell proliferation is mediated by its ability to bind to and sequester Shc, thus uncoupling EGFR signaling from the ras/MAPK pathway. In L-SACC1 mice, we also show that impaired CEACAM1 phosphorylation leads to ligand-independent increase of EGFR-mediated cell proliferation. This appears to be secondary to visceral obesity and the metabolic syndrome, with increased levels of output of free fatty acids and heparin-binding EGF-like growth factor from the adipose tissue of the mice. Thus, L-SACC1 mice provide a model for the mechanistic link between increased cell proliferation in states of impaired metabolism and visceral obesity.
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PMID:CEACAM1 modulates epidermal growth factor receptor--mediated cell proliferation. 1546 33

Elevated circulating fatty acid concentration is a hallmark of insulin resistance and is at least in part attributed to the action of adipose tissue-derived tumor necrosis factor-alpha (TNF-alpha) on lipolysis. Cell death-inducing DFFA (DNA fragmentation factor-alpha)-like effector A (CIDEA) belongs to a family of proapoptotic proteins that has five known members in humans and mice. The action of CIDEA is unknown, but CIDEA-null mice are resistant to obesity and diabetes. We investigated CIDEA in adipose tissue of obese and lean humans and mice. The mRNA was expressed in white human fat cells and in brown mouse adipocytes. The adipose mRNA expression of CIDEA in mice was not influenced by obesity. However, CIDEA expression was decreased twofold in obese humans and normalized after weight reduction. Low adipose CIDEA expression was associated with several features of the metabolic syndrome. Human adipocyte depletion of CIDEA by RNA interference stimulated lipolysis and increased TNF-alpha secretion by a posttranscriptional effect. Conversely, TNF-alpha treatment decreased adipocyte CIDEA expression via the mitogen-activated protein kinase c-Jun NH(2)-terminal kinase. We propose an important and human-specific role for CIDEA in lipolysis regulation and metabolic complications of obesity, which is at least in part mediated by cross-talk between CIDEA and TNF-alpha.
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PMID:A human-specific role of cell death-inducing DFFA (DNA fragmentation factor-alpha)-like effector A (CIDEA) in adipocyte lipolysis and obesity. 1591 94

Adiponectin, a major adipose cytokine, plays a crucial role in the inhibition of metabolic syndrome by acting on such cell types as muscle cells and hepatocytes. Furthermore, evidence suggests that adiponectin may influence cancer pathogenesis. Adiponectin occurs in non-proteolytic (full-length adiponectin: f-adiponectin) and proteolytic (globular adiponectin: g-adiponectin) forms in various oligomeric states. Different forms of adiponectin show distinct biological effects through differential activation of downstream signaling pathways. Here we identify c-Jun NH(2)-terminal kinase (JNK), and signal transducer and activator of transcription 3 (STAT3) as common downstream effectors of f- and g-adiponectin. f- and g-adiponectin both stimulate JNK activation in prostate cancer DU145, PC-3, and LNCaP-FGC cells, hepatocellular carcinoma HepG2 cells, and C2C12 myoblasts. Furthermore, both f- and g-adiponectin drastically suppress constitutive STAT3 activation in DU145 and HepG2 cells. These suggest that JNK and STAT3 may constitute a universal signaling pathway to mediate adiponectin's pathophysiological effects on metabolic syndrome and cancer.
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PMID:Adiponectin activates c-Jun NH2-terminal kinase and inhibits signal transducer and activator of transcription 3. 1593 15

The balance between reactive oxigen species (ROS) production and degradation is important in defining oxidative stress. In aging process, ROS production increases and degradation is impaired and thus oxidative stress is accumulated. Oxidative stress damages organs both directly and indirectly. Protein, lipid, as well as DNA are directly react with ROS, more over, ROS interact with intracellular signaling system. It is reported that several transcription factors such as NF-kappaB, AP-1 and ASK-1 and also it interferes MAPK activity. Besides these signaling, we recently showed that insulin resistance is induced by accumulated oxidative stress in aged mice. Adrenomedullin deficient mice accumulate higher oxidative stress and insulin resistance developed in aging. Oxidative stress in aging relates not only direct organ damage but also induce risk factors for vascular damage such as metabolic syndrome.
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PMID:[Increasing oxidative stress in aging]. 1594 81

Reactive oxygen and nitrogen molecules have been typically viewed as the toxic by-products of metabolism. However, accumulating evidence has revealed that reactive species, including hydrogen peroxide, serve as signaling molecules that are involved in the regulation of cellular function. The chronic and/or increased production of these reactive molecules or a reduced capacity for their elimination, termed oxidative stress, can lead to abnormal changes in intracellular signaling and result in chronic inflammation and insulin resistance. Inflammation and oxidative stress have been linked to insulin resistance in vivo. Recent studies have found that this association is not restricted to insulin resistance in type 2 diabetes, but is also evident in obese, nondiabetic individuals, and in those patients with the metabolic syndrome. An increased concentration of reactive molecules triggers the activation of serine/threonine kinase cascades such as c-Jun N-terminal kinase, nuclear factor-kappaB, and others that in turn phosphorylate multiple targets, including the insulin receptor and the insulin receptor substrate (IRS) proteins. Increased serine phosphorylation of IRS reduces its ability to undergo tyrosine phosphorylation and may accelerate the degradation of IRS-1, offering an attractive explanation for the molecular basis of oxidative stress-induced insulin resistance. Consistent with this idea, studies with antioxidants such as vitamin E, alpha-lipoic acid, and N-acetylcysteine indicate a beneficial impact on insulin sensitivity, and offer the possibility for new treatment approaches for insulin resistance.
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PMID:The molecular basis for oxidative stress-induced insulin resistance. 1599 59


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