Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Medulloblastoma with extensive nodularity (MBEN) is the only type of medulloblastoma (MB), an aggressive CNS tumour of childhood, that is connected with favourable prognosis. In patients with MBEN tumour resection and chemotherapy are sometimes sufficient. While development of other types of MB is usually connected with activation of the wingless pathway, sonic hedgehog pathway or mammalian target of rapamycin (mTor) pathway, little is known about the molecular basis of MBEN pathophysiology. In the present paper we evaluated activation of the mTor pathway and kinases upstream of mTor, mitogen-activated protein kinase (MAPK/Erk) and protein kinase B (PKB/Akt) in an MBEN sample. Using western blot technique with antibodies directed against active, phosphorylated forms of proteins, we found upregulation of mTor, Akt and Erk. Thus we postulate that the mTor pathway, often implicated in the development of CNS tumours, is also responsible for MBEN progression. Especially interesting seems implication of Erk and other kinases belonging to the same pathway: mitogen-activated protein kinase kinase (MEK-1) or phospho-ribosomal S6 kinase-1 (p90 RSK1), whose activity we usually demonstrate in more benign neoplasms. However, it remains to be clarified whether Erk pathway activation is actually prognostic for benign tumour development.
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PMID:Favourable prognosis in medulloblastoma with extensive nodularity is associated with mitogen-activated protein kinase upregulation. 2221 15

Medulloblastoma is the most common malignant brain tumor in children. Recent studies have implicated sonic hedgehog (SHH) and insulin growth factor (IGF) as important mediators in deregulated pathways, which directly inactivate tuberous sclerosis complex, leading to activation of the serine/threonine kinase, mammalian target of rapamycin (mTOR). mTOR consists of two catalytic subunits of biochemically distinct complexes called mTORC1 and mTORC2. This study aims to further elucidate the role of the mTOR pathway, in the development of medulloblastoma, and assess the use of mTOR inhibitors as novel therapeutic agents. Medulloblastoma cells treated with mTORC1 inhibitor, rapamycin, down-regulated pERK expression initially; however ERK activation was evident upon prolonged treatment. Phosphorylation of mTORC1 substrate, p70S6K at thr389 was reduced by rapamycin and pretreatment with rapamycin abrogated platelet-derived growth factor (PDGF)-induced activation of S6K, as well as that of mTORC2 substrate pAKT(Ser473). Activation of AKT was decreased at 1, 3, and 6 h of treatment, but extended treatment with rapamycin increased expression of pAKT(Ser473). Expression of cyclic dependent kinase inhibitor, P27, decreased following PDGF and increased following rapamycin treatment, suggesting their respective impact on cell proliferation via cell cycle control. Cell proliferation was increased by 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment of medulloblastoma cells, while it was suppressed following treatment with rapamycin or U0126 (MEK1/2 inhibitor). pp242, a novel combined mTORC1/2 inhibitor, and rapamycin limited proliferation by reducing the S-Phase entry as assessed by EdU incorporation, while PDGF increased EdU incorporation. pp242 reduced the number of cells entering the S-phase to a greater extent than did rapamycin. Migration of medulloblastoma cells towards fibronectin was suppressed in a time-dependent manner after rapamycin treatment. These results indicate that the mTOR pathway is involved in the pathogenesis of medulloblastoma, and that targeting this pathway may provide a strategy for therapy of medulloblastoma.
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PMID:PI3K/mTOR signaling pathways in medulloblastoma. 2284 85