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941.
Kanzawa N Shimozawa N Wanders RJ Ikeda K Murakami Y Waterham HR Mukai S Fujita M Maeda Y Taguchi R Fujiki Y Kinoshita T 《Journal of lipid research》2012,53(4):653-663
Many cell surface proteins in mammalian cells are anchored to the plasma membrane via glycosylphosphatidylinositol (GPI). The predominant form of mammalian GPI contains 1-alkyl-2-acyl phosphatidylinositol (PI), which is generated by lipid remodeling from diacyl PI. The conversion of diacyl PI to 1-alkyl-2-acyl PI occurs in the ER at the third intermediate in the GPI biosynthetic pathway. This lipid remodeling requires the alkyl-phospholipid biosynthetic pathway in peroxisome. Indeed, cells defective in dihydroxyacetone phosphate acyltransferase (DHAP-AT) or alkyl-DHAP synthase express only the diacyl form of GPI-anchored proteins. A defect in the alkyl-phospholipid biosynthetic pathway causes a peroxisomal disorder, rhizomelic chondrodysplasia punctata (RCDP), and defective biogenesis of peroxisomes causes Zellweger syndrome, both of which are lethal genetic diseases with multiple clinical phenotypes such as psychomotor defects, mental retardation, and skeletal abnormalities. Here, we report that GPI lipid remodeling is defective in cells from patients with Zellweger syndrome having mutations in the peroxisomal biogenesis factors PEX5, PEX16, and PEX19 and in cells from patients with RCDP types 1, 2, and 3 caused by mutations in PEX7, DHAP-AT, and alkyl-DHAP synthase, respectively. Absence of the 1-alkyl-2-acyl form of GPI-anchored proteins might account for some of the complex phenotypes of these two major peroxisomal disorders. 相似文献
942.
Matsuda T Sakaguchi K Hamaguchi R Kobayashi T Abe E Hama Y Hayashi M Honda D Okita Y Sugimoto S Okino N Ito M 《Journal of lipid research》2012,53(6):1210-1222
Thraustochytrids are known to synthesize PUFAs such as docosahexaenoic acid (DHA). Accumulating evidence suggests the presence of two synthetic pathways of PUFAs in thraustochytrids: the polyketide synthase-like (PUFA synthase) and desaturase/elongase (standard) pathways. It remains unclear whether the latter pathway functions in thraustochytrids. In this study, we report that the standard pathway produces PUFA in Thraustochytrium aureum ATCC 34304. We isolated a gene encoding a putative Δ12-fatty acid desaturase (TauΔ12des) from T. aureum. Yeasts transformed with the tauΔ12des converted endogenous oleic acid (OA) into linoleic acid (LA). The disruption of the tauΔ12des in T. aureum by homologous recombination resulted in the accumulation of OA and a decrease in the levels of LA and its downstream PUFAs. However, the DHA content was increased slightly in tauΔ12des-disruption mutants, suggesting that DHA is primarily produced in T. aureum via the PUFA synthase pathway. The transformation of the tauΔ12des-disruption mutants with a tauΔ12des expression cassette restored the wild-type fatty acid profiles. These data clearly indicate that TauΔ12des functions as Δ12-fatty acid desaturase in the standard pathway of T. aureum and demonstrate that this thraustochytrid produces PUFAs via both the PUFA synthase and the standard pathways. 相似文献
943.
944.
Sasakura Y Kanda M Ikeda T Horie T Kawai N Ogura Y Yoshida R Hozumi A Satoh N Fujiwara S 《Development (Cambridge, England)》2012,139(12):2156-2160
Retinoic acid (RA)-mediated expression of the homeobox gene Hox1 is a hallmark of the chordate central nervous system (CNS). It has been suggested that the RA-Hox1 network also functions in the epidermal ectoderm of chordates. Here, we show that in the urochordate ascidian Ciona intestinalis, RA-Hox1 in the epidermal ectoderm is necessary for formation of the atrial siphon placode (ASP), a structure homologous to the vertebrate otic placode. Loss of Hox1 function resulted in loss of the ASP, which could be rescued by expressing Hox1 in the epidermis. As previous studies showed that RA directly upregulates Hox1 in the epidermis of Ciona larvae, we also examined the role of RA in ASP formation. We showed that abolishment of RA resulted in loss of the ASP, which could be rescued by forced expression of Hox1 in the epidermis. Our results suggest that RA-Hox1 in the epidermal ectoderm played a key role in the acquisition of the otic placode during chordate evolution. 相似文献
945.
Higashi TL Ikeda M Tanaka H Nakagawa T Bando M Shirahige K Kubota Y Takisawa H Masukata H Takahashi TS 《Current biology : CB》2012,22(11):977-988
Highlights? XEco2 loading and cohesin acetylation require pre-RC assembly but not DNA synthesis ? Two N-terminal motifs in XEco2 are essential for XEco2 loading and cohesion ? The PIP box in XEco2 contributes to cohesion ? Interaction of acetylated cohesin with DNA is stabilized after DNA replication 相似文献
946.
Ikeda S Tachikawa M Akanuma S Fujinawa J Hosoya K 《American journal of physiology. Gastrointestinal and liver physiology》2012,303(3):G291-G297
Taurine is essential for the hepatic synthesis of bile salts and, although taurine is synthesized mainly in pericentral hepatocytes, taurine and taurine-conjugated bile acids are abundant in periportal hepatocytes. One possible explanation for this discrepancy is that the active supply of taurine to hepatocytes from the blood stream is a key regulatory factor. The purpose of the present study is to investigate and identify the transporter responsible for taurine uptake by periportal hepatocytes. An in vivo bolus injection of [(3)H]taurine into the rat portal vein demonstrated that 25% of the injected [(3)H]taurine was taken up by the liver on a single pass. The in vivo uptake was significantly inhibited by GABA, taurine, β-alanine, and nipecotic acid, a GABA transporter (GAT) inhibitor, each at a concentration of 10 mM. The characteristics of Na(+)- and Cl(-)-dependent [(3)H]taurine uptake by freshly isolated rat hepatocytes were consistent with those of GAT2 (solute carrier SLC6A13). Indeed, the K(m) value of the saturable uptake (594 μM) was close to that of mouse SLC6A13-mediated taurine transport. Although GABA, taurine, and β-alanine inhibited the [(3)H]taurine uptake by > 50%, each at a concentration of 10 mM, GABA caused a marked inhibition with an IC(50) value of 95 μM. The [(3)H]taurine uptake exhibited a significant reduction when the GAT2 gene was silenced. Immunohistochemical analysis showed that GAT2 was localized on the sinusoidal membrane of the hepatocytes predominantly in the periportal region. These results suggest that GAT2 is responsible for taurine transport from the circulating blood to hepatocytes predominantly in the periportal region. 相似文献
947.
948.
Seki T Akita M Kamimura Y Muramatsu S Araki H Sugino A 《The Journal of biological chemistry》2006,281(30):21422-21432
GINS is a protein complex found in eukaryotic cells that is composed of Sld5p, Psf1p, Psf2p, and Psf3p. GINS polypeptides are highly conserved in eukaryotes, and the GINS complex is required for chromosomal DNA replication in yeasts and Xenopus egg. This study reports purification and biochemical characterization of GINS from Saccharomyces cerevisiae. The results presented here demonstrate that GINS forms a 1:1 complex with DNA polymerase epsilon (Pol epsilon) holoenzyme and greatly stimulates its catalytic activity in vitro. In the presence of GINS, Pol epsilon is more processive and dissociates more readily from replicated DNA, while under identical conditions, proliferating cell nuclear antigen slightly stimulates Pol epsilon in vitro. These results strongly suggest that GINS is a Pol epsilon accessory protein during chromosomal DNA replication in budding yeast. Based on these results, we propose a model for molecular dynamics at eukaryotic chromosomal replication fork. 相似文献
949.
Soga T Baran R Suematsu M Ueno Y Ikeda S Sakurakawa T Kakazu Y Ishikawa T Robert M Nishioka T Tomita M 《The Journal of biological chemistry》2006,281(24):16768-16776
Metabolomics is an emerging tool that can be used to gain insights into cellular and physiological responses. Here we present a metabolome differential display method based on capillary electrophoresis time-of-flight mass spectrometry to profile liver metabolites following acetaminophen-induced hepatotoxicity. We globally detected 1,859 peaks in mouse liver extracts and highlighted multiple changes in metabolite levels, including an activation of the ophthalmate biosynthesis pathway. We confirmed that ophthalmate was synthesized from 2-aminobutyrate through consecutive reactions with gamma-glutamylcysteine and glutathione synthetase. Changes in ophthalmate level in mouse serum and liver extracts were closely correlated and ophthalmate levels increased significantly in conjunction with glutathione consumption. Overall, our results provide a broad picture of hepatic metabolite changes following acetaminophen treatment. In addition, we specifically found that serum ophthalmate is a sensitive indicator of hepatic GSH depletion, and may be a new biomarker for oxidative stress. Our method can thus pinpoint specific metabolite changes and provide insights into the perturbation of metabolic pathways on a large scale and serve as a powerful new tool for discovering low molecular weight biomarkers. 相似文献
950.
Ikeda H Omoteyama K Yoshida K Nishi S Sakai M 《The Journal of biological chemistry》2006,281(10):6734-6741
The rat placental glutathione S-transferase (GST-P), an isozyme of glutathione S-transferase, is not expressed in normal liver but is highly induced at an early stage of chemical hepatocarcinogenesis and in hepatomas. Recently, we reported that the NF-E2 p45-related factor 2 (Nrf2)/MafK heterodimer binds to GST-P enhancer 1 (GPE1), a strong enhancer of the GST-P gene, and activates this gene in preneoplastic lesions and hepatomas. In addition to the positive regulation during hepatocarcinogenesis, negative regulatory mechanisms might work to repress GST-P in normal liver, but this remains to be clarified. In this work, we identify the CCAAT enhancer-binding protein alpha (C/EBPalpha) as a negative regulator that binds to GPE1 and suppresses GST-P expression in normal liver. C/EBPalpha binds to part of the GPE1 sequence, and the binding of Nrf2/MafK and C/EBPalpha to GPE1 is mutually exclusive. In a transient-transfection analysis, C/EBPalpha activated GPE1 in F9 embryonal carcinoma cells but strongly inhibited GPE1 activity in hepatoma cells. The expression of C/EBPalpha was specifically suppressed in GST-P-positive preneoplastic foci in the livers of carcinogentreated rats. A chromatin immunoprecipitation analysis showed that C/EBPalpha bound to GPE1 in the normal liver in vivo but did not bind in preneoplastic hepatocytes. Introduction of the C/EBPalpha gene fused with the estrogen receptor ligand-binding domain into hepatoma cells, and subsequent activation by beta-estradiol led to the suppression of endogenous GST-P expression. These results indicate that C/EBPalpha is a negative regulator of GST-P gene expression in normal liver. 相似文献