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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin was initially identified as a regulator of appetite and weight control centers in the hypothalamus, but appears to be involved in a number of physiological processes. This study was carried out to examine the possible role of leptin in regulating prolactin (PRL) release using the teleost pituitary model system. This advantageous system allows isolation of a nearly pure population of lactotropes in their natural, in situ aggregated state. The rostral pars distalis were dissected from tilapia pituitaries and exposed to varying concentrations of leptin (0, 1, 10, 100 nM) for 1 h. Release of PRL was stimulated by leptin in a potent and concentration-dependent manner. A time-course experiment showed that the strongest response in PRL release with leptin occurs within the first hour (approximately sixfold), and stimulation was sustained after 16 h (approximately twofold). Many of the actions of leptin are mediated by the activation of extracellular signal-regulated kinase (ERK1/2) but nothing is known about the cellular mechanisms by which leptin might regulate PRL secretion in vertebrates. We therefore tested whether ERK1/2 might be involved in the leptin PRL response and found that the ERK inhibitor, PD98059, hindered leptin-induced PRL release. We further analyzed leptin response by quantifying tyrosine and threonine phosphorylation of ERK1/2 using western blots. One hour incubation with leptin induced a concentration-dependent increase in phosphorylated, and thus active, ERK1/2. Our data show that leptin is a powerful stimulator of in vitro PRL release and that its actions occur in part through stimulation of ERK1/2.
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PMID:Leptin stimulates pituitary prolactin release through an extracellular signal-regulated kinase-dependent pathway. 1825 50

Excessive fat mass is a risk factor for postmenopausal breast cancer. Leptin, a fat cell-derived peptide hormone, elicits a growth-stimulating effect in breast cancer cells with leptin receptor expression, although the leptin-induced signal in malignant cells is not fully understood. Here, we found that exogenous leptin induced tyrosine phosphorylation of HER2 in SKBR3 cells, which showed marked overexpression of HER2. Phosphorylation of HER2 was detected at 2 min and continued up to 120 min after the start of stimulation. Leptin-induced HER2 phosphorylation was partially reduced by an epidermal growth factor receptor inhibitor, AG1478, or a Janus-activated kinase inhibitor, AG490. Leptin also induced phosphorylation of extracellular signal-regulated kinase 1/2, which was mostly abrogated by a HER2 tyrosine kinase inhibitor, AG825. In a proliferation assay, addition of 500 ng/mL leptin increased the proliferation of SKBR3, which was totally inhibited by AG825. Collectively, our data suggest that leptin can transactivate HER2 through both epidermal growth factor receptor and Janus-activated kinase 2 activation, which can cause the growth of breast cancer cells with HER2 overexpression.
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PMID:Leptin augments proliferation of breast cancer cells via transactivation of HER2. 1826 53

Leptin, a pleiotropic cytokine secreted by adipocytes but also identified in salivary glands and saliva, is recognized as an important element of oral mucosal defense. Here, we report that in sublingual salivary glands leptin protects the acinar cells of against ethanol cytotoxicity. We show that ethanol- induced cytotoxicity, characterized by a marked drop in the acinar cell capacity for NO production, arachidonic acid release and prostaglandin generation, was subject to suppression by leptin. The loss in countering capacity of leptin on the ethanol-induced cytotoxicity was attained with cyclooxygenase inhibitor, indomethacin and nitric oxide synthase (cNOS) inhibitor, L-NAME, as well as PP2, an inhibitor of Src kinase. Indomethacin, while not affecting leptin-induced arachidonic acid release, caused the inhibition in PGE2 generation, pretreatment with L-NAME led to the inhibition in NO production, whereas PP2 exerted the inhibitory effect on leptin-induced changes in NO, arachidonic acid, and PGE2. The leptin-induced changes in arachidonic acid release and PGE2 generation were blocked by ERK inhibitor, PD98059, but not by PI3K inhibitor, wortmannin. Further, leptin suppression of ethanol cytotoxicity was reflected in the increased Akt and cNOS phosphorylation that was sensitive to PP2. Moreover, the stimulatory effect of leptin on the acinar cell cNOS activity was inhibited not only by PP2, but also by Akt inhibitor, SH-5, while wortmannin had no effect. Our findings demonstrate that leptin protection of salivary gland acinar cells against ethanol cytotoxicity involves Src kinase-mediated parallel activation of MAPK/ERK and Akt that result in up-regulation of the respective prostaglandin and nitric oxide synthase pathways.
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PMID:Leptin protection of salivary gland acinar cells against ethanol cytotoxicity involves Src kinase-mediated parallel activation of prostaglandin and constitutive nitric oxide synthase pathways. 1834 Apr 8

The human placenta is prerequisite for the development of gestational hypertensive diseases like early-onset preeclampsia (PE) and Hemolysis, Elevated Liver enzymes and Low platelets (HELLP) syndrome. Both syndromes are associated with extensive maternal and perinatal mortality, and morbidity with life long consequences. We aimed to investigate differences in gene expression between placental tissue obtained from normotensive pregnant women and women with PE and HELLP syndrome. Firstly, comparison of Serial Analysis of Gene Expression profiles of 28 weeks' control placenta (available after idiopathic premature delivery) to a HELLP/PE placenta matched for gestational age identified 404 differentially expressed transcripts. Secondly, using sqPCR, the expression levels of 37 of these transcripts were analyzed in placentas of 36 pregnant women, 22 with preeclampsia and HELLP syndrome. Thirdly, nearest centroid classification determined the HELLP specific molecular signature consisting of the upregulated expression of genes encoding the vascular endothelial growth factor receptor (FLT1), leptin (LEP), pappalysin 2 (PAPPA2), and WW domain containing transcription regulator 1 (WWTR1) combined with down regulated expression of the genes encoding cadherin-associated protein (CTNNAL), glutathione S-transferase pi (GSTP1) and calgranulin A (S100A8). This set discriminates HELLP placenta from control and PE placenta with a 24% misclassification rate (95% CI 8.3-41.9%), independent from known risk factors like parity and ethnicity. The transcripts involved correspond to diverse molecular pathways, exemplifying the multigenic molecular basis of the disorder. This distinct placental molecular signature suggests that HELLP is not a PE variant but a separate disease entity. Our data may prove fundamental for the further molecular analysis of PE and HELLP syndrome.
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PMID:Seven placental transcripts characterize HELLP-syndrome. 1837 11

Adiponectin exerts an insulin-sensitizing effect, improving insulin action in peripheral tissues and restraining insulin resistance. Here, we explore the hypothesis that adiponectin can reproduce some of the actions of insulin/leptin in the hypothalamus. The presence of AdipoR1 and AdipoR2 was mapped to the arcuate and lateral hypothalamic nuclei. Icv adiponectin reduced food intake, which was accompanied by activation/engagement of IRS1/2, ERK, Akt, FOXO1, JAK2 and STAT3. All these actions were dependent on AdipoR1, since inhibition of this receptor, and not of AdipoR2, completely reversed the effects described above. Thus, adiponectin acts in the hypothalamus, activating elements of the canonical insulin and leptin signaling pathways and promoting reduction of food intake.
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PMID:AdipoR1 mediates the anorexigenic and insulin/leptin-like actions of adiponectin in the hypothalamus. 1839 28

Advances in understanding the functional aspects of leptin in the processes affecting peripheral tissues have brought to the forefront the role of this pluripotent cytokine in the processes of gastric mucosal defense and repair. Here, we report that leptin protects the gastric mucosal cells against ethanol cytotoxicity. We show that ethanol cytotoxicity, characterized by a marked drop in the mucosal cells capacity for NO production, arachidonic acid release and prostaglandin generation, was subject to suppression by leptin. The loss in countering capacity of leptin on the ethanol-induced cytotoxicity was attained with cyclooxygenase inhibitor, indomethacin and nitric oxide synthase (cNOS) inhibitor, L-NAME, as well as PP2, an inhibitor of Src kinase. Indomethacin caused the inhibition in PGE(2) generation, pretreatment with L-NAME led to the inhibition in NO production, whereas PP2 exerted the inhibitory effect on leptin-induced changes in NO, arachidonic acid and PGE(2). The leptin-induced changes in arachidonic acid release and PGE(2) generation were blocked by ERK inhibitor, PD98059, but not by PI3K inhibitor, wortmannin. Moreover, the stimulatory effect of leptin on the mucosal cells cNOS activity was inhibited not only by PP2, but also by Akt inhibitor, SH-5. Our findings demonstrate that leptin protection of gastric mucosa against ethanol cytotoxicity involves Src kinase-mediated bifurcated activation of MAPK/ERK and Akt that leads to up-regulation of the respective prostaglandin and nitric oxide synthase pathways.
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PMID:Src kinase-mediated parallel activation of prostaglandin and constitutive nitric oxide synthase pathways in leptin protection of gastric mucosa against ethanol cytotoxicity. 1862 47

Terminally ill insulin-deficient rodents with uncontrolled diabetes due to autoimmune or chemical destruction of beta-cells were made hyperleptinemic by adenoviral transfer of the leptin gene. Within approximately 10 days their severe hyperglycemia and ketosis were corrected. Despite the lack of insulin, moribund animals resumed linear growth and appeared normal. Normoglycemia persisted 10-80 days without other treatment; normal physiological conditions lasted for approximately 175 days despite reappearance of moderate hyperglycemia. Inhibition of gluconeogenesis by suppression of hyperglucagonemia and reduction of hepatic cAMP response element-binding protein, phoshoenolpyruvate carboxykinase, and peroxisome proliferator-activated receptor-gamma-coactivator-1alpha may explain the anticatabolic effect. Up-regulation of insulin-like growth factor 1 (IGF-1) expression and plasma levels and increasing IGF-1 receptor phosphorylation in muscle may explain the increased insulin receptor substrate 1, PI3K, and ERK phosphorylation in skeletal muscle. These findings suggest that leptin reverses the catabolic consequences of total lack of insulin, potentially by suppressing glucagon action on liver and enhancing the insulinomimetic actions of IGF-1 on skeletal muscle, and suggest strategies for making type 1 diabetes insulin-independent.
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PMID:Making insulin-deficient type 1 diabetic rodents thrive without insulin. 1877 78

Obesity is considered one of the risk factors for many cancers. Serum leptin levels are often elevated in obese people. Leptin has been reported to act as a mitogenic agent and promote renal cancer cell proliferation, whereas the detailed mechanisms still remain to be elucidated. The purpose of this study is to investigate the proliferation and mobility effects in leptin-treated Caki-2 renal cell carcinoma and analyze the alterations of leptin-inducible STAT3 pathways and mitogenic signaling ERK pathways. Our results indicate the constitutive expression of leptin receptor could not be upregulated upon the stimulation of leptin in Caki-2 cells. Leptin increases the proliferation and mobility capabilities of Caki-2 cells via upregulating the expression of both phosphor-ERK and phosphor-STAT3 and these two pathways could be partially abolished by inhibition of the activation of JAK-STAT3 and completely abrogated by inhibition of ERK1/2 pathways. Our results also suggest that mitogenic actions of leptin are not the consequence of altered its receptor expression; whereas the cellular proliferation appears to be working through the cross-talking of JAK-STAT3 and ERK1/2 pathways in renal cell carcinoma caki-2 cells.
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PMID:Concomitant activation of the JAK/STAT3 and ERK1/2 signaling is involved in leptin-mediated proliferation of renal cell carcinoma Caki-2 cells. 1878

Leptin mainly acts on the hypothalamus in the brain, in which it regulates food intake and energy expenditure. However, the direct effects of leptin on adipocytes have been controversial in the cellular level. In this study, the effects of leptin on rosiglitazone-induced adipocyte differentiation were investigated in the primary preadipocytes prepared from subcutaneous fat tissues of C57BL/6-Lep(ob/ob) mouse. We found that acute and prolonged treatment of leptin on preadipocytes inhibited the rosiglitazone-induced transcription factor expression and adipocyte differentiation, respectively, accompanied with decreased expression of PPARgamma and aP2. Either PD98059, an ERK inhibitor or fludarabine, a STAT1 inhibitor restored leptin-inhibited PPARgamma expression and subsequent lipid accumulation, but inhibitors for PI-3K (LY294002) and for STAT3 (piceatannol) did not. Furthermore, leptin decreased PPARgamma expression also in fully differentiated adipocytes, which was reversed by either PD98059 or fludarabine. Taken together, these data suggest that leptin has a direct inhibitory effect on the rosiglitazone-induced adipocyte differentiation and PPARgamma expression, in which ERK1/2 MAP kinase and JAK/STAT1 signaling pathways are involved.
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PMID:Leptin inhibits rosiglitazone-induced adipogenesis in murine primary adipocytes. 1879 Jul 15

Several proangiogenic/proinflammatory factors involved in endometrial cancer are regulated by leptin, but the signaling mechanisms responsible for these leptin-induced actions are largely unknown. Here, we report that in benign (primary and HES) and cancerous-endometrial epithelial cells (EEC) (An3Ca, SK-UT2 and Ishikawa), leptin in a dose-dependent manner regulates vascular endothelial growth factor, (VEGF); interleukin-1 beta, (IL-1beta); leukemia inhibitory factor, (LIF) and their respective receptors, VEGFR2, IL-1R tI and LIFR. Remarkably, leptin induces a greater increase in VEGF/VEGFR2 and LIF levels in cancer than in benign cells. However, IL-1beta was only increased by leptin in benign primary-EEC. Cancer-EEC expressed higher levels of leptin receptor (full-length OB-Rb and short isoforms) in contrast to benign primary-EEC. Leptin-mediated activation of JAK2 (janus kinase 2) was upstream to the activation of PI-3K (phosphatidylinositol-3 kinase) and/or MAPK (mitogen-activated protein kinase) signaling pathways. Leptin induction of cytokines/receptors generally involved JAK2 and MAPK activation, but PI-3K phosphorylation was required for leptin increase of LIF, IL-1/IL-1R tI. Leptin-mediated activation of mTOR (mammalian target of Rapamycin), mainly linked to MAPK, played a central role in leptin regulation of all cytokines and receptors. These results suggest that leptin's effects are cell-specific and could confer a proliferative or cell survival advantage or possibly promote endometrial thickness. Leptin's effects on proangiogenic molecules were more evident in malignant versus benign cells and may imply that there is an underlying shift in leptin-induced cell signaling pathways in endometrial cancer cells.
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PMID:Leptin regulation of proangiogenic molecules in benign and cancerous endometrial cells. 1879 54


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