PKM2-dependent beta-catenin transactivation is instrumental in EGFR-promoted tumour cell proliferation and brain tumour development. In addition, positive correlations have been identified between c-Src activity, beta-catenin Y333 phosphorylation and PKM2 nuclear accumulation in human glioblastoma specimens. Furthermore, levels of beta-catenin phosphorylation and nuclear PKM2 have been correlated with grades of glioma malignancy and prognosis. These findings reveal that EGF induces beta-catenin transactivation via a mechanism distinct from that induced by Wnt/Wingless(4) and highlight the essential non-metabolic functions of PKM2 in EGFR-promoted

beta-catenin transactivation, cell proliferation and tumorigenesis.”
“Extensive use of organophosphorous pesticides (OP) by young men represents a public health problem. Toxicity of OP mainly results in neurotoxicity due to their oxygen analogues GSK2126458 nmr Go 6983 mouse (oxons), formed during the OP oxidative activation. OP alter semen quality and sperm chromatin and DNA

at different stages of spermatogenesis. Oxons are more toxic than the parent compounds; however, their toxicity to spermatogenic cells has not been reported. We evaluated sperm DNA damage by several OP compounds and their oxons in human spermatozoa from healthy volunteers incubated with 50-750 mu M of methyl-parathion (MePA), methyl-paraoxon (MePO), chlorpyrifos (CPF), chlorpyrifos-oxon (CPO), diazinon (DZN) or diazoxon (DZO). All concentrations were not cytotoxic (evaluated by eosin-Y exclusion), except 750

p,]VI MePO. Oxons were 15% to 10 times more toxic to sperm DNA(evaluated by the SCSA parameter, %DFI) than their corresponding parent compounds, at the following order: MePO > CPO = MePA > CPF > DZO > DZN, suggesting that oxon metabolites participate in OP sperm genotoxicity. (C) 2008 Elsevier Inc. All rights reserved.”
“During protein synthesis, tRNAs and mRNA move through the ribosome between mTOR inhibitor aminoacyl (A), peptidyl (P), and exit (E) sites of the ribosome in a process called translocation. Translocation is accompanied by the displacement of the tRNAs on the large ribosomal subunit toward the hybrid A/P and P/E states and by a rotational movement (ratchet) of the ribosomal subunits relative to one another. So far, the structure of the ratcheted state has been observed only when translation factors were bound to the ribosome. Using cryo-electron microscopy and classification, we show here that ribosomes can spontaneously adopt a ratcheted conformation with tRNAs in their hybrid states. The peptidyl-tRNA molecule in the A/P state, which is visualized here, is not distorted compared with the A/A state except for slight adjustments of its acceptor end, suggesting that the displacement of the A-site tRNA on the SOS subunit is passive and is induced by the 30S subunit rotation.