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)

The erythroleukemia developed by spi-1/PU.1-transgenic mice is a model of multistage oncogenic process. Isolation of tumor cells representing discrete stages of leukemic progression enables the dissection of some of the critical events required for malignant transformation. To elucidate the molecular mechanisms of multistage leukemogenesis, we developed a microarray transcriptome analysis of nontumorigenic (HS1) and tumorigenic (HS2) proerythroblasts from spi-1-transgenic mice. The data show that transcriptional up-regulation of the sphingosine kinase gene (SPHK1) is a recurrent event associated with the tumorigenic phenotype of these transgenic proerythroblasts. SPHK1 is an enzyme of the metabolism of sphingolipids, which are essential in several biologic processes, including cell proliferation and apoptosis. HS1 erythroleukemic cells engineered to overexpress the SPHK1 protein exhibited growth proliferative advantage, increased clonogenicity, and resistance to apoptosis in reduced serum level by a mechanism involving activation of the extracellular signal-related kinases 1/2 (ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. In addition, SPHK1-overexpressing HS1 cells acquired tumorigenicity when engrafted in vivo. Finally, enforced expression of a dominant-negative mutant of SPHK1 in HS2 tumorigenic cells or treatment with a pharmacologic inhibitor reduced both cell growth and apoptosis resistance. Altogether, these data suggest that overexpression of the sphingosine kinase may represent an oncogenic event during the multistep progression of an erythroleukemia.
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PMID:Overexpression of sphingosine kinase 1 is an oncogenic event in erythroleukemic progression. 1589 Jun 87

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