Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The prolonged treatment with phorbol 12-myristate 13-acetate (PMA) of a human megakaryoblastic leukemia cell line, MEG-O1, induced increase of sphingosine kinase (SPHK) enzyme activity and SPHK1 protein expression as well as SPHK1 message. Protein kinase C (PKC) inhibitor prevented the PMA-induced SPHK1 gene expression. To elucidate the regulatory mechanism of this gene expression, we examined the promoter area (distal to the first exon) and its binding proteins. Luciferase analyses showed that the area of 300 bp from the first exon was sufficient for PMA-responsiveness, and that specificity protein 1 (Sp1)- and two activator protein 2 (AP-2)-binding motifs within this area were necessary for responsiveness. Inhibitors for PKC and MEK1 decreased this PMA-induced promoter activity. Electrophoresis mobility shift assay (EMSA) showed that Sp1 protein was originally bound to the Sp1 site and that two additional bands bound to the two AP-2 motifs were observed only when stimulated with PMA in MEG-O1 cells. The appearance of these bands resulted from binding to an unknown protein rather than AP-2. These results indicated that PMA up-regulates SPHK1 gene expression through PMA-responsive elements of the 5' promoter area of the gene, and suggested that PMA-mediated SPHK1 gene expression would be mediated via PKC- and ERK-dependent signal transduction pathway by binding the transcription factor to AP-2 motifs.
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PMID:Regulation of sphingosine kinase 1 gene expression by protein kinase C in a human leukemia cell line, MEG-O1. 1472 73

RET, the receptor of glial cell line-derived neurotrophic factor (GDNF) family ligands, is important for the development of kidney and peripheral neurons. GDNF promotes survival and differentiation of neurons. Mutation of RET leads to the constitutive signal activation causing papillary thyroid carcinoma and multiple endocrine neoplasia type 2 (MEN2). In this study, we report that GDNF/RET signaling up-regulates sphingosine kinase (SPHK) enzyme activity, SPHK1 protein and SPHK1 message in TGW human neuroblastoma cells. Silencing of SPHK1 using siRNA inhibited GDNF-induced neurite formation, GAP43 expression, and cell growth, suggesting the important role of SPHK1 in GDNF signal transduction. Furthermore, NIH3T3 cells transfected with MEN2A type mutated RET but not c-RET demonstrated the up-regulation of SPHK activity, SPHK1 protein and SPHK1 message compared with NIH3T3 cells. The cell growth and anchorage-independent colony formation of MEN2A-NIH3T3 was inhibited with siRNA of SPHK1, while no effect of scramble siRNA was observed. These results suggest the oncogenic role of SPHK1 in MEN2A type tumor. Promoter analysis showed that activator protein 2 and specificity protein 1 binding motif of the 5' promoter region of SPHK1 gene is important for its induction by GDNF. Furthermore, we demonstrated that ERK1/2 and PI3 kinase are involved in GDNF-induced SPHK1 transcription by using specific inhibitors.
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PMID:RET signaling-induced SPHK1 gene expression plays a role in both GDNF-induced differentiation and MEN2-type oncogenesis. 1755 48

Cholangiocarcinoma (CCA) is characterized by a uniquely aggressive behavior and lack of effective targeted therapies. After analyzing the gene expression profiles of seven paired intrahepatic CCA microarrays, a novel sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) pathway and a novel target gene, SPHK1, were identified. We hypothesized that therapeutic targeting of this pathway can be used to kill intrahepatic cholangiocarcinoma (CCA) cells. High levels of SPHK1 protein expression, which was evaluated by immunohistochemical staining of samples from 96 patients with intrahepatic CCA, correlated with poor overall survival. The SPHK1 inhibitor SK1-I demonstrated potent antiproliferative activity in vitro and in vivo. SK1-I modulated the balance of ceramide-sphinogosine-S1P and induced CCA apoptosis. Furthermore, SK1-I combined with JTE013, an antagonist of the predominant S1P receptor S1PR2, inhibited the AKT and ERK signaling pathways in CCA cells. Our preclinical data suggest SPHK1/S1P pathway targeting may be an effective treatment option for patients with CCA.
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PMID:Identification of SPHK1 as a therapeutic target and marker of poor prognosis in cholangiocarcinoma. 2609 Jul 20