Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.25 (MEKK1)
 1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rapid proliferation of atypical megakaryoblasts is a characteristic of megakaryoblastic leukemia. Cells from patients with this disorder and cell lines established from this type of leukemia showed the presence of gelsolin but the absence of scinderin expression, 2 filamentous actin-severing proteins present in normal megakaryocytes and platelets. Vector-mediated expression of scinderin in the megakaryoblastic cell line MEG-01 induced a decrease in both F-actin and gelsolin. This was accompanied by increased Rac2 expression and by activation of the PAK/MEKK.SEK/JNK/c-jun, c-fos transduction pathway. The Raf/MEK/ERK pathway was also activated in these cells. Transduction pathway activation was followed by cell differentiation, polyploidization, maturation, and apoptosis with release of platelet-like particles. Particles expressed surface CD41a antigen (glycoprotein IIb/IIIa or fibrinogen receptor), had dense bodies, high-affinity serotonin transport, and circular array of microtubules. Treatment of particles with thrombin induced serotonin release and aggregation that was blocked by CD41a antibodies. PAC-1 antibodies also blocked aggregation. Exposure of cells to PD98059, a blocker of MEK, inhibited antigen CD41a expression, increases in cell volume, and number of protoplasmic extensions. Cell proliferation and cell ability to form tumors in nude mice were also inhibited by the expression of scinderin. MEG-01 cells expressing scinderin had the same fate in vivo as in culture. Thus, when injected into nude mice, they entered apoptosis and released platelet-like particles. The lack of scinderin expression in megakaryoblastic leukemia cells seems to be responsible for their inability to enter into differentiation and maturation pathways characteristic of their normal counterparts.
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PMID:Expression of scinderin in megakaryoblastic leukemia cells induces differentiation, maturation, and apoptosis with release of plateletlike particles and inhibits proliferation and tumorigenesis. 1156 9

Monoamine oxidases (MAO) A and B deaminate a number of biogenic amines. Aberrant expression of MAO is implicated in several psychiatric and neurogenerative disorders. In this study, we have shown that phorbol 12-myristate 13-acetate (PMA) increases human MAO B, but not MAO A, gene expression. The sequence between -246 and -225 bp consists of overlapping binding sites (Sp1/Egr-1/Sp1) that are recognized by Sp1, Sp3, and PMA-inducible Egr-1 is essential for PMA activation. PMA transiently increases egr-1 and c-jun gene expression. Mutation studies show that Egr-1 and c-Jun transactivate the MAO B promoter and increase endogenous MAO B transcripts via the Sp1/Egr-1/Sp1 overlapping binding sites. Sp3 inhibits Sp1 and Egr-1 activation of MAO B gene expression. c-fos gene expression was increased by PMA but not involved in MAO B gene transcription. Furthermore, protein kinase C inhibitor blocks the PMA-dependent activation of MAO B. Co-transfection of the MAO B promoter with dominant negative forms of Ras, Raf-1, MEKK1, MEK1, MEK3, MEK7, ERK2, JNK1, and p38/RK inhibit the PMA-dependent activation of the MAO B promoter. These results indicate that MAO B expression is selectively induced by the activation of protein kinase C and MAPK signaling pathway and that c-Jun and Egr-1 appear to be the ultimate targets of this regulation.
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PMID:Activation of human monoamine oxidase B gene expression by a protein kinase C MAPK signal transduction pathway involves c-Jun and Egr-1. 1195 20

WD40 repeat proteins play important roles in a variety of cellular functions, including cell growth, proliferation, apoptosis, and intracellular signal transduction. Mitogen-activated protein kinases (MAPKs) are evolutionary conserved enzymes in cell signal transduction connecting cell-surface receptors to critical regulatory targets within cells and control cell survival, adaptation, and proliferation. Previous studies revealed that G-protein coupled receptors (GPCRs) play important roles in the signal transduction from extracellular stimuli to MAPKs and the WD40-containing Gbeta proteins as well as Gbeta-like proteins are involved in the stimulation and regulation of the MAPK signaling pathways. Here we report the identification and characterization of a novel human WD40 repeat protein, WD40 repeat protein 26 (WDR26). The cDNA of WDR26 is 3,729 bp, encoding a Gbeta-like protein of 514 amino acids in the cytoplasm. The protein is highly conserved in evolution across different species from yeast, Drosophila, mouse, to human. Northern blot analysis indicates that WDR26 is expressed in most of the examined human tissues, especially at a high level in skeletal muscle. Overexpression of WDR26 in the cell inhibits the transcriptional activities of ETS proteins, ELK-1 and c-fos serum response element (SRE), mediated by MEKK1. These results suggest that WDR26 may act as a negative regulator in MAPK signaling pathway and play an important role in cell signal transduction.
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PMID:WDR26: a novel Gbeta-like protein, suppresses MAPK signaling pathway. 1537 3

Tumor progression locus-2 (Tpl-2) kinase is a member of the mitogen-activated protein kinase kinase kinase family that has been implicated in cellular transformation. The enhanced expression of this protein has been shown to activate both the mitogen-activated protein kinase and c-Jun N-terminal kinase pathways. However, the molecular mechanisms responsible for the oncogenic potential of Tpl-2 are still largely unknown. Here, we showed that Tpl-2 interacted with p53 both in vitro and ex vivo. The overexpression of Tpl-2 inhibited the epidermal growth factor (EGF)-induced p53 phosphorylation (Ser15) through upregulating the activity of protein phosphatase 2A, which interacted with p53 stimulated by EGF. Also, the EGF-induced p53 activity was suppressed in the Tpl-2 wild-type (WT)-transfected HEK 293 cells, but had no effect in the Tpl-2-mutant (S413A)-transfected cells. Furthermore, introduction of small interfering RNA-Tpl-2 into HEK 293 cells resulted in decreased cell viability compared with only adenovirus-p53-infected cells. In addition, the Tpl-2 WT, but not Tpl-2 mutant (S413A), showed increased EGF-induced c-fos promoter activity, followed by activator protein 1 (AP-1) transactivation activity, which was associated with the cell transformation prompted by the H-Ras-Tpl-2-AP-1 signaling axis. These results indicated that the Ser413 of Tpl-2 plays an important role in EGF-induced carcinogenesis as well as inactivation of the p53.
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PMID:Tpl-2 kinase downregulates the activity of p53 and enhances signaling pathways leading to activation of activator protein 1 induced by EGF. 1922 Oct 2


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