Akiyoshi Fukamizu

University of Tsukuba, Tsukuba, Ibaraki, Japan

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Publications (337)1560.68 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Molecular pathways regulating the development of arterial and venous endothelial cells (ECs) are now well established, but control of parallel arterial-venous alignment is unclear. Here we report that arterial-venous alignment in the skin is determined by apelin receptor (APJ) expression in venous ECs. One of the activators of APJ is apelin. We found that apelin is produced by arterial ECs during embryogenesis, induces chemotaxis of venous ECs, and promotes the production of secreted Frizzled-related protein 1 (sFRP1) by APJ(+) ECs. sFRP1 stimulates matrix metalloproteinase production by Ly6B.2(+) neutrophil-like cells located between the arteries and veins, resulting in remodeling of extracellular matrices to support venous displacement. Moreover, using apelin- or APJ-deficient mice, which exhibit arterial-venous disorganization, we found that arterial-venous alignment is involved in thermoregulation, possibly by regulating countercurrent heat exchange. We hypothesize that the evolution of parallel juxtapositional arterial-venous alignment was an adaptation to reduce body heat loss. Copyright © 2015 Elsevier Inc. All rights reserved.
    Developmental Cell 04/2015; 33(3). DOI:10.1016/j.devcel.2015.02.024 · 10.37 Impact Factor
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    ABSTRACT: Apelin peptide is an endogenous ligand of APJ (a putative receptor protein related to the angiotensin receptor AT1), which is a member of a G-protein-coupled receptor superfamily with seven transmembrane domains. Recent findings have suggested that the apelin-APJ system plays a potential role in cardiac contraction and cardioprotection. Here we show that the apelin-APJ system is disrupted in doxorubicin (Dox)-induced cardiotoxicity. We found downregulation of apelin and APJ mRNA expressions in C57Bl/6J mouse hearts on days 1 and 5 after Dox administration (20 mg/kg, i.p.). Plasma apelin levels and cardiac APJ protein expression were significantly decreased on day 5 after Dox injection. Cardiac apelin contents were reduced on day 1, but increased to the basal levels on day 5 after Dox injection. We also examined the effects of APJ gene deletion on Dox-induced cardiotoxicity. Compared with wild-type mice, APJ knockout mice showed significant depression in cardiac contractility on day 5 after Dox treatment (15 mg/kg, i.p.), followed by a decrease in 14-day survival rates. Moreover, Dox-induced myocardial damage, cardiac protein carbonylation, and autophagic dysfunction were accelerated in APJ knockout mice. Rat cardiac H9c2 cells showed Dox-induced decreases in viability, which were prevented by APJ overexpression and the combination with apelin treatment. These results suggest that the suppression of APJ expression after Dox administration can exacerbate Dox-induced cardiotoxicity, which may be responsible for depressed protective function of the endogenous apelin-APJ system. Modulation of the apelin-APJ system may hold promise for treating the Dox-induced cardiotoxicity. Copyright © 2014, American Journal of Physiology - Heart and Circulatory Physiology.
    AJP Heart and Circulatory Physiology 02/2015; 308(8):ajpheart.00703.2013. DOI:10.1152/ajpheart.00703.2013 · 4.01 Impact Factor
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    ABSTRACT: Phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine (PC), the most abundant phospholipids of plasma membrane, resulting in the production of choline and phosphatidic acid (PA). Choline is a precursor of the neurotransmitter acetylcholine, whereas PA functions as an intracellular lipid mediator of diverse biological functions. For assessing PLD activity in vitro, PLD-derived choline has been often analyzed with radioactive or non-radioactive methods. In this study, we have developed a new method for detecting choline and PA with MALDI-QIT-TOF/MS by using 9-aminoacridine as a matrix. The standard calibration curves showed that choline and PA could be detected with linearity over the range from 0.05 and 1 pmol, respectively. Importantly, this method enables the concomitant detection of choline and PA as a reaction product of PC hydrolysis by PLD2 proteins. Thus, our simple and direct method would be useful to characterize the enzymatic properties of PLD, thereby providing insight into mechanisms of PLD activation.
    Bioscience Biotechnology and Biochemistry 06/2014; 78(6):981-8. DOI:10.1080/09168451.2014.910102 · 1.21 Impact Factor
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    ABSTRACT: Abstract Renin is predominantly expressed in juxtaglomerular cells in the kidney and regulates blood pressure homeostasis. To examine possible in vivo functions of a mouse distal enhancer (mdE), we generated transgenic mice (TgM) carrying either wild-type or mdE-deficient renin BACs (bacterial artificial chromosome), integrated at the identical chromosomal site. In the kidneys of the TgM, the mdE contributed 80% to basal renin promoter activity. To test for possible physiological roles for the mdE, renin BAC transgenes were used to rescue the hypotensive renin-null mice. Interestingly, renal renin expression in the Tg(BAC):renin-null compound mice was indistinguishable between the wild-type and mutant BAC carriers. Surprisingly, however, the plasma renin activity and angiotensin I concentration in the mdE compound mutant mice were significantly lower than the same parameters in the control mice, and the mutants were consistently hypotensive, demonstrating that blood pressure homeostasis is regulated through transcriptional cis elements controlling renin activity.
    Journal of Receptor and Signal Transduction Research 04/2014; DOI:10.3109/10799893.2014.908917 · 1.61 Impact Factor
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    ABSTRACT: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyze the transfer of methyl groups from S-adenosyl-L-methionine to nitrogen atoms on arginine residues. Here, we describe the crystal structure of Caenorhabditis elegans PRMT7 in complex with its reaction product S-adenosyl-L-homocysteine. The structural data indicated that PRMT7 harbors two tandem repeated PRMT core domains that form a novel homodimer-like structure. S-adenosyl-L-homocysteine bound to the N-terminal catalytic site only; the C-terminal catalytic site is occupied by a loop that inhibits cofactor binding. Mutagenesis demonstrated that only the N-terminal catalytic site of PRMT7 is responsible for cofactor binding.
    FEBS letters 04/2014; DOI:10.1016/j.febslet.2014.03.053 · 3.34 Impact Factor
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    ABSTRACT: Abstract Context: There are few short-term mouse models of chronic obstructive pulmonary disease (COPD) mimicking the human disease. In addition, p38 is recently recognized as a target for the treatment of COPD. However, the precise mechanism how p38 contributes to the pathogenesis of COPD is still unknown. Objective: We attempted to create a new mouse model for COPD by intra-tracheal administration of a mixture of lipopolysaccharide (LPS) and cigarette smoke solution (CSS), and investigated the importance of the p38 mitogen-activated protein kinase (p38) pathway in the pathogenesis of COPD. Methods: Mice were administered LPS + CSS once a day on days 0-4 and 7-11. Thereafter, CSS alone was administered to mice once a day on days 14-18. On day 28, histopathological changes of the lung were evaluated, and bronchoalveolar lavage fluid (BALF) was subjected to western blot array for cytokines. Transgenic (TG) mice expressing a constitutive-active form of MKK6, a p38-specific activator in the lung, were subjected to our experimental protocol of COPD model. Results: LPS + CSS administration induced enlargement of alveolar air spaces and destruction of lung parenchyma. BALF analyses of the LPS + CSS group revealed an increase in expression levels of several cytokines involved in the pathogenesis of human COPD. These results suggest that our experimental protocol can induce COPD in mice. Likewise, histopathological findings of the lung and induction of cytokines in BALF from MKK6 c.a.-TG mice were more marked than those in WT mice. Conclusion: In a new experimental COPD mouse model, p38 accelerates the development of emphysema.
    Journal of Receptor and Signal Transduction Research 03/2014; DOI:10.3109/10799893.2014.896380 · 1.61 Impact Factor
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    ABSTRACT: Agenesis of the corpus callosum (ACC) is a congenital abnormality of the brain structure. More than 60 genes are known to be involved in corpus callosum development. However, the molecular mechanisms underlying ACC are not fully understood. Previously, we produced a novel transgenic mouse strain, TAS, carrying genes of the tetracycline-inducible expression system that are not involved in brain development, and inherited ACC was observed in the brains of all homozygous TAS mice. Although ACC was probably induced by transgene insertion mutation, the causative gene and the molecular mechanism of its pathogenesis remain unclear. Here, we first performed interphase three-color fluorescence in situ hybridization (FISH) analysis to determine the genomic insertion site. Transgenes were inserted into chromosome 18 similar to 12.0 Mb from the centromere. Gene expression analysis and genomic PCR walking showed that the genomic region containing exon 4 of Cables1 was deleted by transgene insertion and the other exons of Cables1 were intact. The mutant allele was designated as Cables1(TAS). Interestingly, Cables1(TAS) mRNA consisted of exons 1-3 of Cables1 and part of the transgene that encoded a novel truncated Cables1 protein. Homozygous TAS mice exhibited mRNA expression of Cables1(TAS) in the fetal cerebrum, but not that of wild-type Cables1. To investigate whether a dominant negative effect of Cables1(TAS) or complete loss of function of Cables1 gives rise to ACC, we produced Cables1-null mutant mice. ACC was not observed in Cables1-null mutant mice, suggesting that a dominant negative effect of Cables1(TAS) impairs callosal formation. Moreover, ACC frequency in Cables1(+/TAS) mice was significantly lower than that in Cables1(-/TAS) mice, indicating that wild-type Cables1 interfered with the dominant negative effect of Cables1(TAS). This study indicated that truncated Cables1 causes ACC and wild-type Cables1 contributes to callosal formation.
    Laboratory Investigation 12/2013; 94(3). DOI:10.1038/labinvest.2013.146 · 3.83 Impact Factor
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    ABSTRACT: Angiotensin converting enzyme 2 (ACE2) is a negative regulator of the renin-angiotensin system (RAS), catalyzing the conversion of Angiotensin II to Angiotensin 1-7. Apelin is a second catalytic substrate for ACE2 and functions as an inotropic and cardioprotective peptide. While an antagonistic relationship between the RAS and apelin has been proposed, such functional interplay remains elusive. Here we found that ACE2 was downregulated in apelin-deficient mice. Pharmacological or genetic inhibition of angiotensin II type 1 receptor (AT1R) rescued the impaired contractility and hypertrophy of apelin mutant mice, which was accompanied by restored ACE2 levels. Importantly, treatment with angiotensin 1-7 rescued hypertrophy and heart dysfunctions of apelin-knockout mice. Moreover, apelin, via activation of its receptor, APJ, increased ACE2 promoter activity in vitro and upregulated ACE2 expression in failing hearts in vivo. Apelin treatment also increased cardiac contractility and ACE2 levels in AT1R-deficient mice. These data demonstrate that ACE2 couples the RAS to the apelin system, adding a conceptual framework for the apelin-ACE2-angiotensin 1-7 axis as a therapeutic target for cardiovascular diseases.
    The Journal of clinical investigation 11/2013; DOI:10.1172/JCI69608 · 13.77 Impact Factor
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    ABSTRACT: Mono-allelic expression at the mouse IGF2/H19 locus is controlled by differential allelic DNA methylation of the imprinting control region (ICR). Because a randomly integrated H19 ICR fragment, when incorporated into the genome of transgenic mice (TgM), was allele-specifically methylated in somatic, but not in germ cells, it was suggested that allele-discriminating epigenetic signature, set within or somewhere outside of the Tg H19 ICR fragment in germ cells, was later translated into a differential DNA methylation pattern. To test if the chicken β-globin HS4 (cHS4) chromatin insulator might interfere with methylation imprinting establishment at the H19 ICR, we inserted the H19 ICR fragment, flanked by a set of floxed cHS4 core sequences, into a human β-globin locus YAC and generated TgM (insulated ICR' TgM). As controls, the cHS4 sequences were removed from one side (5'HS4-deleted ICR') or both sides (pseudo-WT ICR') of the insulated ICR' by in vivo cre-loxP recombination. The data show that while maternally inherited transgenic H19 ICR was not methylated in insulated ICR' TgM, it was significantly methylated upon paternal transmission, though the level was lower than in the pseudo-WT ICR' control. Because this reduced level of methylation was also observed in the 5'HS4-deleted ICR' TgM, we speculate that the phenotype is due to VEZF1-dependent demethylation activity, rather than the insulator function, borne in cHS4. Collectively, although we cannot rule out the possibility that cHS4 is incapable of blocking an allele-discriminating signal from outside of the transgene, the epigenetic signature appears to be marked intrinsically within the H19 ICR.
    PLoS ONE 09/2013; 8(9):e73925. DOI:10.1371/journal.pone.0073925 · 3.53 Impact Factor
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    ABSTRACT: Lung surfactant is a complex mixture of lipids and proteins, which is secreted from the alveolar type II epithelial cell and coats the surface of alveoli as a thin layer. It plays a crucial role in the prevention of alveolar collapse through its ability to reduce surface tension. Under normal conditions, surfactant homeostasis is maintained by balancing its release and the uptake by the type II cell for recycling and the internalization by alveolar macrophages for degradation. Little is known about how the surfactant pool is monitored and regulated. Here we show, by an analysis of gene-targeted mice exhibiting massive accumulation of surfactant, that Ig-Hepta/GPR116, an orphan receptor, is expressed on the type II cell and sensing the amount of surfactant by monitoring one of its protein components, surfactant protein D, and its deletion results in a pulmonary alveolar proteinosis and emphysema-like pathology. By a coexpression experiment with Sp-D and the extracellular region of Ig-Hepta/GPR116 followed by immunoprecipitation, we identified Sp-D as the ligand of Ig-Hepta/GPR116. Analyses of surfactant metabolism in Ig-Hepta(+/+) and Ig-Hepta(-/-) mice by using radioactive tracers indicated that the Ig-Hepta/GPR116 signaling system exerts attenuating effects on (i) balanced synthesis of surfactant lipids and proteins and (ii) surfactant secretion, and (iii) a stimulating effect on recycling (uptake) in response to elevated levels of Sp-D in alveolar space.
    PLoS ONE 07/2013; 8(7):e69451. DOI:10.1371/journal.pone.0069451 · 3.53 Impact Factor
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    ABSTRACT: Abnormal methylation at the maternally inherited H19 imprinted control region (H19 ICR) is one of the causative alterations leading to pathogenesis of Beckwith-Wiedemann syndrome (BWS). Recently, it was shown in human BWS patients, as well as mouse cell culture experiments, that Sox-Oct motifs (SOM) in the H19 ICR might play a role in protecting the maternal ICR from de novo DNA methylation. By grafting a mouse H19 ICR fragment into a human β-globin yeast artificial chromosome (YAC) followed by analysis in transgenic mice (TgM), we showed previously that the fragment carried sufficient information to establish and maintain differential methylation after fertilization. To examine possible functions of the SOM in the establishment and/or maintenance of differential methylation, two kinds of YAC-TgM were generated in this study. In the ΔSOM TgM, carrying the mouse H19 ICR bearing an SOM deletion, a maternally inherited transgenic ICR exhibited increased levels of methylation around the deletion site, in comparison to the wild-type control, after implantation. In the λ+CTCF+b (LCb) TgM, carrying a 2.3 kb λ DNA fragment supplemented with the fragment b including the SOM and four CTCF binding sites, maternally- and some of the paternally-inherited LCb fragments were significantly less methylated when compared with a control λ+CTCF fragment that was supplemented only with additional CTCF sites; the λ+CTCF was substantially methylated regardless of the parent of origin after implantation. These results demonstrated that the SOM in the maternal H19 ICR was required for maintaining surrounding sequences in the unmethylated state in vivo.
    Human Molecular Genetics 07/2013; DOI:10.1093/hmg/ddt311 · 6.68 Impact Factor
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    ABSTRACT: Renal dysfunction is accelerated by various factors such as hypertension, aging and diabetes. Glomerular hyper-filtration, considered one of the major risk factors leading to diabetic nephropathy, is often encountered in diabetic patients. However, the interrelationship of these risk factors during the course and development of renal dysfunction has not been fully elucidated. In this study, the effects of aging and uninephrectomy (UNx)-induced hyperfiltration on renal changes were investigated in Tsukuba hypertensive mice (THM) carrying both human renin and angiotensinogen genes. In THM, the urinary albumin/creatinine (Alb/Cr) ratio was elevated with age without a concomitant increase in the plasma Cr concentration. Moreover, the urinary neutrophil gelatinase-associated lipocalin/Cr (NGAL/Cr) ratio, the renal monocyte chemoattractant protein-1 (MCP-1) mRNA expression and the renal collagen type I α 2 (COL1A2) mRNA expression were also increased with age. Age-related albuminuria in THM is likely caused by renal tubular damage, enhanced inflammatory response and tubulointerstitial fibrosis. Furthermore, following UNx, the urinary Alb/Cr ratio and the plasma Cr concentration were increased in THM. The urinary NGAL/Cr ratio and the renal MCP-1 and COL1A2 mRNA expression were not affected by UNx. These results suggested that UNx-induced albuminuria in THM was caused by glomerular dysfunction, rather than renal tubular injury. In conclusion, this study demonstrated for the first time the effects of aging and UNx on renal changes in THM. These findings strongly reinforce the significance of applying a diversity of therapeutic approaches to the management of renal dysfunction.
    05/2013; 1(3):359-364. DOI:10.3892/br.2013.74
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    ABSTRACT: Apelin is the endogenous ligand of APJ, which belongs to the family of G protein‑coupled receptors. Apelin and APJ are highly expressed in various cardiovascular tissues, including the heart, kidney and vascular endothelial and smooth muscle cells. Although apelin exerts hypotensive effects via activation of endothelial nitric oxide synthase (eNOS), the ability of apelin to regulate blood pressure under pathological conditions is poorly understood. In the current study, NG‑nitro‑L‑arginine methyl ester (L‑NAME), a potent NOS inhibitor, was administered chronically, to induce peripheral vascular damage in mice. L‑NAME‑treated mice exhibited hypertension, increased vascular cell adhesion molecule‑1 and plasminogen activator inhibitor‑1 mRNA levels in the aorta and impaired vasodilatation associated with decreased aortic eNOS expression, consistent with endothelial damage. Three days following withdrawal of L‑NAME treatment, the blood pressure response to apelin stimulation was assessed. Although apelin reduced blood pressure in non‑treated mice, it was found to transiently elevate blood pressure in L‑NAME‑treated mice. These results indicate that apelin functions as a vasopressor peptide under pathological conditions, including vascular endothelial dysfunction in mice.
    Molecular Medicine Reports 03/2013; 7(5). DOI:10.3892/mmr.2013.1378 · 1.48 Impact Factor
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    ABSTRACT: Abstract S-adenosyl-L-methionine (SAM) is an intermediate metabolite of methionine and serves as the methyl donor for many biological methylation reactions. The synthesis of SAM is catalyzed by SAM synthetase (SAMS), which transfers the adenosyl moiety of adenosine-5'-triphosphate to methionine. In the nematode Caenorhabditis elegans, four sams family genes, sams-1, -3, -4 and -5, are predicted to encode SAMS proteins. However, their physiological roles remain unclear. Here we show that the four predicted SAMS proteins in fact have the ability to catalyze the formation of SAM in vitro, and revealed that only sams-1 mutant animals among the family genes exhibited a significant reduction in egg-laying. Using transgenic animals carrying a transcriptional reporter for each sams gene promoter, we observed that each sams promoter confers a distinct expression pattern with respect to tissue, time of expression and expression level (i.e. promoter specificity). Promoter-swap experiments revealed that the ectopic expression of SAMS-3, -4 or -5 driven by the sams-1 promoter completely rescued egg-laying in sams-1 mutants. These data indicate that SAMS protein function is conserved throughout the entire family.
    Journal of Receptor and Signal Transduction Research 01/2013; DOI:10.3109/10799893.2012.756896 · 1.61 Impact Factor
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    ABSTRACT: Preeclampsia is a serious complication during pregnancy, and recent epidemiological studies indicate the association between preeclampsia and cardiac morbidity and mortality during the postpartum period. Although the risk of cardiovascular diseases in the postpartum period is affected by lactation, its role in maternal heart with a history of preeclampsia remains unclear. In this study, we investigated postpartum change in cardiac remodeling and function of pregnancy-associated hypertensive (PAH) mice with and without lactation. The systolic blood pressure was increased in PAH mice at day 19 of gestation (E19) and was reduced to normal levels in both lactating and nonlactating (NL) groups in the postpartum period. Histological analyses revealed that cardiac hypertrophy and macrophage infiltration in PAH mice at E19 were improved in both lactating and NL groups at 4 weeks postpartum (4W-PP), while marked fibrosis remained. Increased mRNA expression of profibrotic genes and proinflammatory cytokines in PAH mice at E19 was significantly reduced in both lactating and NL groups at 4W-PP. Echocardiographic analysis found no significant differences in fractional shortening between PAH mice and C57BL/6J mice at E19. On the other hand, at 4W-PP, NL PAH mice showed normal fractional shortening, but lactating PAH mice exhibited significant decreases in cardiac contractility compared with NL PAH mice. These results show that cardiac remodeling induced by hypertension during pregnancy are improved in the postpartum period except fibrosis, whereas lactation induces cardiac contractile dysfunction in mice with a history of pregnancy-associated hypertension.
    Endocrinology 12/2012; 154(2). DOI:10.1210/en.2012-1789 · 4.64 Impact Factor
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    ABSTRACT: In the mouse Igf2/H19 imprinted locus, differential methylation of the imprinting control region (H19 ICR) is established during spermatogenesis and is maintained in offspring throughout development. Previously, however, we observed that the paternal H19 ICR when analyzed in yeast artificial chromosome transgenic mice (YAC-TgM) was preferentially methylated only after fertilization. To identify the DNA sequences that confer methylation imprinting, we divided the H19 ICR into two fragments (1.7 and 1.2 kb) and ligated them to both ends of a λ DNA fragment into which CTCF binding sites had been inserted, and analyzed in YAC-TgM. The maternally inherited λ sequence, normally methylated after implantation in the absence of H19 ICR sequences, became hypomethylated, demonstrating protection-against-methylation activity within the ICR. Meanwhile, the paternally inherited λ sequence was hyper-methylated before implantation only when a 1.7-kb fragment was ligated. Consistently, when two sub-fragments of the H19 ICR were individually investigated for their activities in YAC-TgM, only the 1.7-kb fragment was capable of introducing paternal allele-specific DNA methylation. These results show that post-fertilization methylation imprinting is conferred by a paternal allele-specific methylation activity present in a 1.7-kb DNA fragment of the H19 ICR, while maternal allele-specific activities protect the allele from de novo DNA methylation.
    Molecular and Cellular Biology 12/2012; DOI:10.1128/MCB.01003-12 · 5.04 Impact Factor
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    ABSTRACT: Angiotensin II is involved in tumor growth; however, the precise mechanism is not known. Platelets also contribute to tumor growth, and angiotensin II type 1 receptor (AT1) is expressed on the platelet surface. We hypothesized that interaction of platelets with tumor cells through AT1 receptor signaling promotes tumor metastasis. B16F1 melanoma cells were intravenously injected into Agtr1a knockout mice (AT1a(-/-)) and wild-type littermates (WT); the AT1a(-/-) mice exhibited a reduction in lung colonies. Angiotensin II induced expression of P-selectin on platelets in WT but not in AT1a(-/-) mice. A selective P-selectin neutralizing antibody decreased lung colony numbers in WT but not in AT1a(-/-) mice. Levels of vascular endothelial growth factor (VEGF) and stromal cell-derived factor 1 (SDF-1) receptor in platelets at metastatic locus were lower in AT1a(-/-) mice. Treatment of neutralizing antibodies against VEGF and CXCR4 decreased lung colony numbers in WT but not in AT1a(-/-) mice. In AT1a(-/-) mice, and both mobilization of progenitor cells expressing CXCR4(+)VEGFR1(+) cells from bone marrow and their recruitment to lung tissues were suppressed. These results suggest that AT1A signaling plays a critical role in tumor metastasis through P-selectin-mediated interactions of platelets with tumor and endothelial cells and through the AT1A signaling-dependent production of VEGF and SDF-1, which may be involved in mobilization of CXCR4(+)VEGFR1(+) cells.
    American Journal Of Pathology 12/2012; 182(2). DOI:10.1016/j.ajpath.2012.10.026 · 4.60 Impact Factor
  • Keiji Tanimoto, Akiyoshi Fukamizu
    Nippon rinsho. Japanese journal of clinical medicine 09/2012; 70(9):1466-70.
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    ABSTRACT: Histamine (HA), a mediator of inflammation, type I allergic responses and neurotransmission, is synthesized from L-histidine, the reaction of which is catalyzed by histidine decarboxylase (HDC). HDC has been reported to be induced by various stimuli, not only in mast cells and basophils, but also in T lymphocytes and macrophages. Although its mRNA has been shown to be increased in Jurkat cells when treated with phorbol 12-myristate 13-acetate (TPA), little is known concerning the induced production of HA by HDC. The present study quantified the trace amounts of intracellular HA using ultra-high liquid chromatography in combination with the 6-aminoquinoline carbamate-derivatization technique. To test whether the cellular level of HA is elevated by the induction of HDC in Jurkat cells treated with TPA, the peak corresponding to authentic HA in the cell lysate was fractioned and its molecular weight determined by matrix-assisted laser desorption/ionization quadrupole ion trap time-of-flight mass spectrometry. The results of this study show that the HA level is increased by the induction of HDC expression by TPA in Jurkat cells. Therefore, this method is useful in elucidating the physiological significance of HA production.
    Molecular Medicine Reports 08/2012; 6(5):944-8. DOI:10.3892/mmr.2012.1049 · 1.48 Impact Factor
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    ABSTRACT: Allele-specific methylation of the endogenous H19 imprinting control region (ICR) is established in sperm. We previously showed that the paternal H19 ICR in yeast artificial chromosome (YAC) transgenic mice (TgM) was preferentially methylated in somatic cells, but not in germ cells, suggesting that differential methylation could be established after fertilization. In this report, we discovered small RNA molecules in growing oocytes, the nucleotide sequences of which mapped to the H19 ICR. To test if these small RNA sequences play a role in the establishment of differential methylation, we deleted the sequences from the H19 ICR DNA and generated YAC TgM. In somatic cells of these mice, methylation imprinting of the transgene was normally established. In addition, the mutant fragment was not methylated in sperm and eggs. These data demonstrate that sequences in the H19 ICR that correspond to the small RNA sequences are dispensable for methylation imprinting in YAC TgM.
    Gene 08/2012; 508(1):26-34. DOI:10.1016/j.gene.2012.07.062 · 2.08 Impact Factor

Publication Stats

11k Citations
1,560.68 Total Impact Points


  • 1986–2015
    • University of Tsukuba
      • • Institute of Applied Biochemistry
      • • School of Medicine
      Tsukuba, Ibaraki, Japan
  • 2012
    • Chiba University
      • Department of Biochemistry and Molecular Pharmacology
      Chiba-shi, Chiba-ken, Japan
  • 2010
    • Mitsubishi Tanabe Pharma Corporation
      Ōsaka, Ōsaka, Japan
  • 2007
    • University of Michigan
      • Department of Cell and Developmental Biology
      Ann Arbor, Michigan, United States
  • 2001–2007
    • St. Marianna University School of Medicine
      • • Institute of Medical Science
      • • Department of Medicine
      Kawasaki Si, Kanagawa, Japan
  • 2006
    • The Jikei University School of Medicine
      Edo, Tōkyō, Japan
  • 1992–2006
    • Yokohama City University
      • Department of Medicine
      Yokohama, Kanagawa, Japan
  • 2005
    • Tokyo Medical and Dental University
      Edo, Tōkyō, Japan
    • Kagoshima University
      • Department of Dermatology
      Kagosima, Kagoshima, Japan
  • 2004
    • Teijin
      Edo, Tōkyō, Japan
    • Hokkaido University
      Sapporo, Hokkaidō, Japan
  • 2003
    • Tsukuba Research Institute
      Edo, Tōkyō, Japan
  • 1999
    • Tokyo Kasei University
      Edo, Tōkyō, Japan