Although adaptive systems of immunity against tumor initiation and destruction are well investigated, less understood is the role, if any, of endogenous factors that have conventional functions. Here we show that glycyl-tRNA synthetase (GRS), an essential component of the translation apparatus, circulates in serum and can be secreted from macrophages in response to Fas ligand that is released from tumor cells. Through cadherin (CDH)6 (K-cadherin), GRS bound to different ERK-activated tumor cells, and released phosphatase 2A (PP2A) from CDH6. The activated PP2A then suppressed ERK signaling through dephosphorylation of ERK and induced apoptosis. These activities were inhibited by blocking GRS with a soluble fragment of CDH6. With in vivo administration of GRS, growth of tumors with a high level of CDH6 and ERK activation were strongly suppressed. Our results implicate a conventional cytoplasmic enzyme in translation as an intrinsic component of the defense against ERK-activated tumor formation.A s ancient proteins that arose as part of the development of the genetic code, aminoacyl-tRNA synthetases (AARSs) are essential components of the translation apparatus. The 20 enzymes, 1 for each amino acid, catalyze the attachment of each amino acid to its cognate tRNA in the cytoplasm, where the charged tRNAs are then used for ribosomal protein synthesis (1). Surprisingly, ex-translational functions have been discovered for many tRNA synthetases, including gene regulation in Escherichia coli, RNA splicing in mitochondria of Neurospora crassa (2), and a diverse variety of functions in vertebrates that include among others regulation of inflammatory responses and of angiogenesis (3). These expanded functions are associated with the accretive additions of specialized motifs and domainssuch as internal short sequence motifs and appended GST, leucine zipper, and helix-turn-helix domains (4). The specialized motif and domain additions facilitate new protein-protein interactions that confer novel functions. Some of the many disease connections to AARSs, and to proteins that are part of the multi-tRNA synthetase complex in mammalian cells, are thought to result from disruptions to, or alterations of, their ex-translational functions (5, 6). Indeed, there are dominant CharcotMarie-Tooth disease-causing mutations in tyrosyl-and glycyltRNA synthetases that do not disrupt aminoacylation activity (7,8).Also surprising for essential components of the translation apparatus was the observation that specific fragments (produced by alternative splicing or natural proteolysis) of tyrosyl-and tryptophanyl-tRNA synthetases (YRS and WRS) bind to and signal through extracellular receptors, including chemokine receptor 1 and 2 (CXCR1 and -2) on polymorphonuclear leukocyte (PMN) cells (YRS) (9) and vascular endothelial (VE)-cadherin on endothelial cells (WRS) (10). These two synthetases are secreted from mammalian cells under specific conditions that potentiate their ex-translational functions (11, 12). Collectively, these observations raised th...

Xanthorrhizol, a natural sesquiterpenoid isolated from the rhizome of Curcuma xanthorrhiza Roxb (Zingiberaceae), has antibacterial activities and protective effects against cisplatin-induced hepatotoxicity. In this study, we investigated the activities of xanthorrhizol as an antioxidant or antiinflammatory agent using neuronal and microglial cells. Xanthorrhizol had potent neuroprotective effects on glutamate-induced neurotoxicity and reactive oxygen species (ROS) generation in the murine hippocampal HT22 cell line. Also, xanthorrhizol inhibited H(2)O(2)-induced lipid peroxidation in rat brain homogenates. The properties of xanthorrhizol as an antiinflammatory agent were investigated in microglial activation by lipopolysaccharide. It reduced the expression of cyclooxygenase-2 and the inducible nitric oxide synthase, which consequently resulted in the reduction of nitric oxide. The production of proinflammatory cytokines, such as interleukin-6 and tumor necrosis factor-alpha in activated microglial cells, was reduced by xanthorrhizol. These results suggest that xanthorrhizol could be an effective candidate for the treatment of Alzheimer's disease- and other neurological disease-related ROS and inflammation.

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Learning strategy selection was assessed in two different inbred strains of mice, C57BL/6 and DBA/2, which are used for developing genetically modified mouse models. Male mice received a training protocol in a water maze using alternating blocks of visible and hidden platform trials, during which mice escaped to a single location. After training, mice were required to choose between the spatial location where the platform had been during training (a place strategy) and a visible platform presented in a new location (a cued/response strategy). Both strains of mice had similar escape performance on the visible and hidden platform trials during training. However, in the strategy preference test, C57BL/6 mice selected a place strategy significantly more often than DBA/2 mice. Because much evidence implicates the hippocampus and striatum as important neural substrates for spatial/place and cued/response learning, respectively, the engagement of the hippocampus was then assessed after either place or cue training by determining levels of cAMP response element-binding protein (CREB) and phosphorylated CREB (pCREB) in these two mouse strains. Results revealed that hippocampal CREB levels in both strains of mice were significantly increased after place in comparison to cued training. However, the relation of hippocampal pCREB levels to training was strain dependent; pCREB was significantly higher in C57BL/6 mice than in DBA/2 mice after place training, while hippocampal pCREB levels did not differ between strains after cued training. These findings indicate that pCREB, specifically associated with place/spatial training, is closely tied to differences in spatial/place strategy preference between C57BL/6 and DBA/2 mice.Studies with humans and rodents have shown that different neural systems are involved in the ability to learn tasks that depend on information about either place (i.e., spatial/place) and associations between discrete cues and behavioral responses (i.e

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