The G protein-coupled receptor (GPCR) family is highly diversified and involved in many forms of information processing. SREB2 (GPR85) is the most conserved GPCR throughout vertebrate evolution and is expressed abundantly in brain structures exhibiting high levels of plasticity, e.g., the hippocampal dentate gyrus. Here, we show that SREB2 is involved in determining brain size, modulating diverse behaviors, and potentially in vulnerability to schizophrenia. Mild overexpression of SREB2 caused significant brain weight reduction and ventricular enlargement in transgenic (Tg) mice as well as behavioral abnormalities mirroring psychiatric disorders, e.g., decreased social interaction, abnormal sensorimotor gating, and impaired memory. SREB2 KO mice showed a reciprocal phenotype, a significant increase in brain weight accompanying a trend toward enhanced memory without apparent other behavioral abnormalities. In both Tg and KO mice, no gross malformation of brain structures was observed. Because of phenotypic overlap between SREB2 Tg mice and schizophrenia, we sought a possible link between the two. Minor alleles of two SREB2 SNPs, located in intron 2 and in the 3 UTR, were overtransmitted to schizophrenia patients in a family-based sample and showed an allele load association with reduced hippocampal gray matter volume in patients. Our data implicate SREB2 as a potential risk factor for psychiatric disorders and its pathway as a target for psychiatric therapy.gene manipulation ͉ memory ͉ SNPs T he SREB (superconserved receptor expressed in brain) family of SREB1 (GPR27), SREB2 (GPR85), and SREB3 (GPR173) is a unique subfamily of G protein-coupled receptor (GPCR) selectively expressed in neurons (1-5). Intriguing features of the SREB family include its high degree of sequence conservation throughout vertebrate evolution and its abundant expression in brain structures showing high levels of plasticity, for example the hippocampal dentate gyrus. Among these three members, SREB2 is the most conserved-the primary amino acid sequence is 100% identical among humans, rats, and mice. SREB1 and SREB3 are also highly conserved in mammals. Despite the extraordinary conservation rate in vertebrates, SREB orthologues are not encoded in the genome sequence of Caenorhabditis elegans or Drosophila melanogaster (3).The history of drug discovery has proven that GPCRs are excellent therapeutic targets (6, 7). Although efforts have been made to identify endogenous ligand(s) for SREB, they have been unsuccessful (3). Recent progress in understanding of GPCR physiology has, however, enabled screening of drug candidates for promising GPCRs without knowledge of their endogenous ligands, e.g., screening compounds by using constitutively active mutants (8) or ligand-induced conformational change (9). Thus, if their physiological function is clarified, and their link to the pathophysiology of diseases is demonstrated, then newly discovered GPCRs, even orphan GPCRs like SREB2, become promising drug targets. The distinct features of SREB2, namel...

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Survivin is responsible for cancer progression and drug resistance in many types of cancer. YM155 selectively suppresses the expression of survivin and induces apoptosis in cancer cells in vitro and in vivo. However, the mechanism underlying these effects of YM155 is unknown. Here, we show that a transcription factor, interleukin enhancer-binding factor 3 (ILF3)/NF110, is a direct binding target of YM155. The enhanced survivin promoter activity by overexpression of ILF3/NF110 was attenuated by YM155 in a concentration-dependent manner, suggesting that ILF3/NF110 is the physiological target through which YM155 mediates survivin suppression. The results also show that the unique C-terminal region of ILF3/NF110 is important for promoting survivin expression and for high affinity binding to YM155.

YM-216391, a novel cytotoxic cyclic peptide, has been isolated from the cultured mycelium of Streptomyces nobilis JCM 4274. The planar structure of YM-216391 was assigned on the basis of 1D and 2D NMR spectroscopic techniques. The absolute configuration of the amino acid residues in YM-216391 was determined by Marfey's analysis and chiral HPLC analysis of its acid hydrolysate.

The concentration of neutrophil elastase increased in the urine of the IC patient subset with bladder pain and small bladder capacity.

To search for biomarkers of IgA nephropathy, protein profiles of urine samples from patients with IgA nephropathy and normal volunteers were compared using twodimensional DIGE. Most of the 172 spots identified in the urine were serum proteins, and their amounts in IgA nephropathy urine were much higher than those in normal urine; this can be explained as proteinuria caused by glomerular dysfunction. However, only ␣ 1 -microglobulin, also one of the major serum proteins, in IgA nephropathy urine was not higher in amount than that in normal urine. We confirmed using ELISA analysis that the amounts of transferrin and albumin in IgA nephropathy and diabetic nephropathy urine were much higher than those in normal urine, whereas the amount of ␣ 1 -microglobulin in IgA nephropathy urine was not higher than that in normal urine and was much lower than that in diabetic nephropathy urine. Approximately 50% of ␣ 1 -microglobulin forms a complex with IgA in serum. These results suggest that ␣ 1 -microglobulin in IgA nephropathy urine is a characteristic protein and might be a biomarker for IgA nephropathy and that ␣ 1 -microglobulin might have a relationship with IgA nephropathy pathology. Molecular & Cellular Proteomics 6:738 -744, 2007.

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Peptides U 0400 YM-216391, a Novel Cytotoxic Cyclic Peptide from Streptomyces nobilis. Part 2. Physico-Chemical Properties and Structure Elucidation. -(SOHDA*, K.-Y.; HIRAMOTO, M.; SUZUMURA, K.-I.; TAKEBAYASHI, Y.; SUZUKI, K.-I.; TANAKA, A.; J. Antibiot. 58 (2005) 1, 32-36; Inst. Drug Discovery Res., Yamanouchi Pharm. Co., Ltd., Itabashi, Tokyo 174, Japan; Eng.) -C. Oppel 22-193