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)

The hematopoietic cytokine erythropoietin (Epo) prevents neuronal death during ischemic events in the brain and in neurodegenerative diseases, presumably through its antiapoptotic effects. To explore the role of different signaling pathways in Epo-mediated antiapoptotic effects in differentiated human neuroblastoma SH-SY5Y cells, we employed a prolactin receptor (PrlR)/erythropoietin receptor (EpoR) chimera system, in which binding of prolactin (Prl) to the extracellular domain activates EpoR signaling in the cytosol. On induction of apoptosis by staurosporine, Prl supports survival of the SH-SY5Y cells expressing the wild-type PrlR/EpoR chimera. In these cells Prl treatment strongly activates the STAT5, AKT, and MAPK signaling pathways and induces weak activation of the p65 NF-kappaB factor. Selective mutation of the eight tyrosine residues of the EpoR cytoplasmic domain results in impaired or absent activation of either STAT5 (mutation of Tyr(343)) or AKT (mutation of Tyr(479)) or both (mutation of all eight tyrosine residues). Most interestingly, Prl treatment does not prevent apoptosis in cells expressing mutant PrlR/EpoR chimeras in which either the STAT5 or the AKT signaling pathways are not activated. In contrast, ERK 1/2 is fully activated by all mutant PrlR/EpoR chimeras, comparable with the level seen with the wild-type PrlR/EpoR chimera, implying that activation of the MAPK signaling pathway per se is not sufficient for antiapoptotic activity. Therefore, the antiapoptotic effects of Epo in neuronal cells require the combinatorial activation of multiple signaling pathways, including STAT5, AKT, and potentially MAPK as well, in a manner similar to that observed in hematopoietic cells.
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PMID:Antiapoptotic effects of erythropoietin in differentiated neuroblastoma SH-SY5Y cells require activation of both the STAT5 and AKT signaling pathways. 1640 71

Mesenchymal cells are successfully used to create cell-loaded devices in tissue engineering. Molecular properties of the cells and interaction with polymer scaffolds regulate the development of desired tissues. The present study compared the molecular markers in mesenchymal pleuripotent C3H10T1/2 and osteogenic MBA-15 cells. The cells express transcription factors (TF) of chondro-ostegenic pathway (cbfa-1 and c-fos) and MyoD - TF of muscle differentiation pathway, but not myogenin. Analyzed cells expressed receptors for glucocorticoids, growth hormone, prolactin, and PTH, which indicates their potential responsiveness to systemic signals. Analysis of mRNA encoding for receptors of TGFbeta, TNF, and various interleukins revealed differential expression of IL-2r and TGFbeta-1r receptors, which were expressed by MBA-15 but not by C3H10T1/2 cells. Expression of functional genes indicates differences in the stages of cell differentiation: ALK was present in MBA-15 only, while both cell types expressed collagen-I. Furthermore, we evaluated the expression of adhesion proteins that mediate cell-polymer interactions by flow cytometry analysis. Cell adhesion molecules (CAMs) analyzed were integrinalpha-M (CD11b), selectin-E (CD62E), and PECAM-1 (CD31), which have shown differential expression on cells cultured on plastic, poly(L-lactic acid) (PLLA) or poly(DL-lactide-glycolide acid) (PDLGA) polymer films. Detailed molecular characterization of mesenchymal cells will enable optimization of culture conditions for successful creation of implantable cell-loaded constructs.
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PMID:Molecular and cellular characterization of mesenchymal progenitors for skeletal biomedical devices. 1657 7

The 7 signal transducer and activator of transcription (STAT) molecules are responsible for the transcription of a variety of regulatory and differentiation proteins. STAT 5a is activated through a variety of mechanisms; in the breast, this is predominantly through binding of prolactin to its receptor. Previously, we showed that STAT 5a expression is decreased in atypical and malignant breast ductal epithelial cells. Interestingly, STAT 5a overexpression was observed in cells undergoing secretory change. In this study, secretory carcinomas were examined by immunohistochemistry for the presence of STAT 5a. In contrast to usual in situ or invasive ductal carcinoma, which lacked STAT 5a expression, all secretory carcinomas (11 invasive and 7 in situ, including 4 cases with both) expressed STAT 5a. No expression was seen in apocrine metaplasia or in other specialized breast carcinomas, such as mucinous or clear cell carcinoma. This retention of signal in the secretory carcinomas may be explained by the higher STAT 5a concentration present in cells undergoing secretory changes in general. Alternatively, STAT 5a expression may be related to the t(12;15)(p13;q25) chromosomal translocation, associated with certain pediatric tumors and recently demonstrated in many secretory carcinomas of the breast, which results in the expression of a tyrosine kinase through ETV6 and NTRK3 fusion. ETV6 also has been associated with the STAT 5a signaling pathway in another gene translocation and may be altering STAT 5a expression in secretory carcinomas. Breast cancer causes significant morbidity and mortality, and, regardless of the mechanism for retention of STAT 5a expression in this uncommon variant, the examination of STAT 5a will aid our understanding of normal and abnormal breast tissues.
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PMID:STAT 5a expression in the breast is maintained in secretory carcinoma, in contrast to other histologic types. 1664 57

Differentiation of mammary epithelium in vivo requires signaling through prolactin- and ErbB4/HER4-dependent mechanisms; how these pathways intersect is unknown. We show herein that HC11 mouse mammary cells undergo ErbB4-dependent lactational differentiation. Prolactin and the ErbB4 ligand HB-EGF each induced STAT5A activation, expression of lactogenic differentiation markers, and lumen formation in three-dimensional Matrigel cultures in HC11 cells. ErbB4 undergoes ligand-dependent transmembrane domain cleavage at Val-675, releasing a soluble 80-kDa intracellular domain (s80(HER4)) that localizes to nuclei; the physiological relevance of s80(HER4) is unknown. A HER4(V675A) mutant abolishing transmembrane cleavage impaired STAT5A activity, lactogenic gene expression, and lumen formation. Kinase-dead HER4(KD) was neither cleaved nor able to induce differentiation of HC11 cells. Without treating HC11 cells with prolactin or HB-EGF, s80(HER4) (expressed from a cDNA construct) localized to the nucleus, activated STAT5A, and induced three-dimensional lumen formation. Nuclear localization of exogenous s80(HER4) required intact kinase activity of s80(HER4), as did activation of STAT5A. In contrast, nuclear localization of s80(HER4) and STAT5A activation did not require the 16-amino acid region of the ErbB4 intracellular domain specific to the Cyt-1 isoform of ErbB4, and absent in the Cyt-2 isoform. These results suggest that s80(HER4) formation contributes to ErbB4-dependent differentiation of mammary epithelial cells.
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PMID:The intracellular domain of ErbB4 induces differentiation of mammary epithelial cells. 1683 52

We have demonstrated that S179D prolactin (PRL) is potently antiangiogenic in vivo. Here, we examined apoptosis in human endothelial cells, using procaspase-8 and cytochrome c release as markers of the extrinsic and intrinsic pathways, respectively. Both pathways converge at caspase-3, which is responsible for cleavage of DNA fragmentation factor (DFF45). A 3-d incubation in 50 ng/ml S179D PRL quadrupled the number of early apoptotic cells; this effect was doubled at 100 ng/ml and became maximal at 500 ng/ml. DFF45 and procaspase 8 cleavage were detectable at 100 ng/ml. Cytochrome c, however, was unaffected until 500 ng/ml. The p21 increased at 24 h, whereas a change in p53 required both triple the time and higher doses. The p21 promoter activity was maximal at 50 ng/ml, whereas 500 ng/ml were required to see a significant change in the Bax promoter (a measure of p53 activity). Because S179D PRL and basic fibroblast growth factor (bFGF) have both been shown to activate ERK, the effect of S179D PRL on bFGF-induced ERK signaling was examined. S179D PRL blocked ERK phosphorylation in response to bFGF, whereas continued coincubation caused a delayed and prolonged activation of ERK. PD98059 inhibited this delayed activation of ERK and effects of S179D PRL on all measures except p53 levels or activity of the Bax promoter. We conclude that S179D PRL blocks bFGF-induced ERK signaling and yet uses ERK in a different time frame to elevate p21 and activate the extrinsic pathway. Prolonged incubations and high concentrations additionally activate the intrinsic pathway using an alternate intracellular signal.
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PMID:S179D prolactin primarily uses the extrinsic pathway and mitogen-activated protein kinase signaling to induce apoptosis in human endothelial cells. 1684 May 47

Acute myeloid leukemia (AML) with translocation t(8;16)(p11;p13) is an infrequent leukemia subtype with characteristic clinicobiological features. This translocation leads to fusion of MYST3 (MOZ) and CREBBP (CBP) genes, probably resulting in a disturbed transcriptional program of a myelomonocytic precursor. Nonetheless, its gene expression profile is unknown. We have analyzed the gene expression profile of 23 AML patients, including three with molecularly confirmed MYST3-CREBBP fusion gene, using oligonucleotide U133A arrays (Affymetrix). MYST3-CREBBP cases clustered together and clearly differentiated from samples with PML-RARalpha, RUNX1-RUNX1T1, and CBFbeta-MYH11 rearrangements. The relative expression of 46 genes, selected according to their differential expression in the high-density array study, was analyzed by low-density arrays in an additional series of 40 patients, which included 7 MYST3-CREBBP AML cases. Thus, genes such as prolactin (PRL) and proto-oncogene RET were confirmed to be specifically overexpressed in MYST3-CREBBP samples whereas genes such as CCND2, STAT5A, and STAT5B were differentially underexpressed in this AML category. Interestingly, MYST3-CREBBP AML exhibited a characteristic pattern of HOX expression, with up-regulation of HOXA9, HOXA10, and cofactor MEIS1 and marked down-regulation of other homeobox genes. This profile, with overexpression of FLT3, HOXA9, MEIS1, AKR7A2, CHD3, and APBA2, partially resembles that of AML with MLL rearrangement. In summary, this study shows the distinctive gene expression profile of MYST3-CREBBP AML, with overexpression of RET and PRL and a specific pattern of HOX gene expression.
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PMID:Gene expression profiling of acute myeloid leukemia with translocation t(8;16)(p11;p13) and MYST3-CREBBP rearrangement reveals a distinctive signature with a specific pattern of HOX gene expression. 1684 38

The extracellular adherence protein (Eap), a broad-spectrum adhesin secreted by Staphylococcus aureus, was previously shown to curb acute inflammatory responses, presumably through its binding to endothelial cell (EC) ICAM-1. Examining the effect of Eap on endothelial function in more detail, we here show that, in addition, Eap functions as a potent angiostatic agent. Concomitant treatment of EC with purified Eap resulted in the complete blockage of the mitogenic and sprouting responses elicited by vascular endothelial growth factor (VEGF)165 or basic fibroblast growth factor (bFGF). Moreover, the induction of tissue factor and decay-accelerating factor were repressed by Eap, as determined by qRT-polymerase chain reaction (qRT-PCR), with a corresponding reduction in Egr-1 protein up-regulation seen. This angiostatic activity was accompanied by a corresponding inhibition in ERK1/2 phosphorylation, while activation of p38 was not affected. Inhibition occurred downstream of tyrosine kinase receptor activation, as comparable effects were seen on TPA-induced ERK1/2 phosphorylation. Similar to previously described angiostatic agents like angiopoietin-1 or the 16-kDa prolactin fragment, Eap blockage of the Ras/Raf/MEK/ERK cascade was localized by pull-down assay at the level of Ras activation. Eap's combined anti-inflammatory and antiangiogenic properties render this bacterial protein not only an important virulence factor during S. aureus infection but open new perspectives for therapeutic applications in pathological neovascularization.
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PMID:The extracellular adherence protein from Staphylococcus aureus abrogates angiogenic responses of endothelial cells by blocking Ras activation. 1707 91

Psoriasis vulgaris is an autoimmune dermatosis characterized by type 1 T cell infiltration. Prolactin may be involved in the pathogenesis of psoriasis. CXC ligand 9 (CXCL9), CXCL10, and CXCL11 recruit type 1 T cells, and their production by keratinocytes is enhanced in psoriatic lesions. CXCL9, CXCL10, and CXCL11 production by keratinocytes depends on nuclear factor-kappaB (NF-kappaB) and signal transducer and activator of transcription (STAT)1 and that of CXCL11 depends on interferon (IFN)-regulatory factor (IRF)-1. We examined in vitro effects of prolactin on CXCL9, CXCL10, and CXCL11 production in human keratinocytes. Although prolactin alone was ineffective, it enhanced IFN-gamma-induced secretion and mRNA expression of CXCL9, CXCL10, and CXCL11 in parallel to the activation of STAT1, NF-kappaB, and IRF-1. Inhibitors of Janus kinase (JAK), p38 MAPK, and MAPK/ERK kinase (MEK) suppressed prolactin- plus IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production and NF-kappaB, STAT1, and IRF-1 activities. Prolactin induced phosphorylation of JAK2 and ERK, whereas IFN-gamma induced phosphorylation of JAK1, JAK2, and p38 MAPK. Prolactin modestly or IFN-gamma greatly induced tyrosine phosphorylation of STAT1, and both were suppressed by JAK inhibitor. Prolactin modestly or IFN-gamma greatly induced serine phosphorylation of STAT1, which was suppressed by MEK or p38 MAPK inhibitor, respectively. Prolactin induced phosphorylation of inhibitory kappaBalpha and NF-kappaB p65, which was suppressed by MEK inhibitor. These results suggest that prolactin may enhance IFN-gamma-induced CXCL9, CXCL10, and CXCL11 production in keratinocytes via activation of STAT1, NF-kappaB, and IRF-1 through JAK2 and MEK/ERK pathways. Prolactin may promote type 1 T cell infiltration into psoriatic lesions via these chemokines.
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PMID:Prolactin enhances interferon-gamma-induced production of CXC ligand 9 (CXCL9), CXCL10, and CXCL11 in human keratinocytes. 1725 1

Prolactin has been associated with many effects and has been implicated in the pathogenesis of pregnancy-related hypertensive disorders, although little is known about its vascular effects. The present study was designed to determine the primary effect of prolactin on regional vascular beds and the mechanisms involved. In 37 anesthetized pigs, the infusion of 0.17 mug/kg min of prolactin at constant heart rate and arterial pressure decreased coronary, mesenteric, renal, and iliac blood flow. This response was graded in further five pigs by increasing the infused dose of the hormone between 0.017 and 1 mug/kg min. In 22 of the 37 pigs, blockade of cholinergic receptors (five pigs) and of alpha-adrenoceptors (five pigs) did not affect the prolactin-induced vascular response, which was abolished by blockade of beta(2)-adrenoceptors (five pigs) and by blockade of vascular nitric oxide (NO) synthase (seven pigs). In 15 of the 37 pigs the increases in measured blood flows caused by iv infusion of isoproterenol (five pigs) and by intraarterial administration of acetylcholine (five pigs) and of sodium nitroprusside (five pigs) were significantly reduced by infusion of prolactin. Moreover, the treatment of porcine aortic endothelial cells by prolactin caused a reduction of NO production and of the phosphorylation of ERK, Akt, and p38, which was prevented by the concomitant treatment by the beta(2)-adrenergic agonist albuterol. The present study showed that iv infusion of prolactin primarily caused coronary, mesenteric, renal, and iliac vasoconstriction. These effects were brought about by the inhibition of a vasodilatory beta(2)-adrenergic receptor-mediated effect related to the NO intracellular pathway.
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PMID:Prolactin induces regional vasoconstriction through the beta2-adrenergic and nitric oxide mechanisms. 1746 60

An association between physical activity and premenopausal breast cancer risk may be due, in part, to relationships with sex hormones or growth factors. Therefore, we assessed whether MET-h/week of total physical activity (moderate-to-vigorous intensity), walking, or vigorous physical activity, and h/week of standing or sitting were associated with plasma concentrations of several hormones. We examined levels of estrogens, androgens, progesterone, prolactin, sex hormone binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), IGF binding protein-3, and growth hormone (GH) in 565 premenopausal women, ages 33-52 years, from the Nurses' Health Study II (NHSII). About 87% of women had both timed follicular and luteal samples; other women had one untimed sample. In general we observed few associations between sex hormone or IGF levels and measures of physical activity or inactivity. However, free testosterone was modestly inversely associated with total physical activity (p-trend = 0.02). Luteal estradiol, free estradiol, and estrone also were inversely associated with total physical activity (p-trend = 0.10, 0.04, 0.01, respectively); however, the trend was substantially attenuated when excluding women with anovulatory cycles or irregular cycles. These cross-sectional results suggest that physical activity and inactivity have limited associations with premenopausal sex hormone and growth factor levels, except possibly luteal estrogens.
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PMID:Physical activity and inactivity in relation to sex hormone, prolactin, and insulin-like growth factor concentrations in premenopausal women - exercise and premenopausal hormones. 1754 94


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