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The CLN9 protein, a regulator of dihydroceramide synthase

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dc.contributor.author Schulz A.
dc.contributor.author Mousallem T.
dc.contributor.author Venkataramani M.
dc.contributor.author Persaud-Sawin D.-A.
dc.contributor.author Zucker A.
dc.contributor.author Luberto C.
dc.contributor.author Bielawska A.
dc.contributor.author Bielawski J.
dc.contributor.author Holthuis J.C.M.
dc.contributor.author Jazwinski S.M.
dc.contributor.author Kozhaya L.
dc.contributor.author Dbaibo G.S.
dc.contributor.author Boustany R.-M.N.
dc.contributor.editor
dc.date Feb-2006
dc.date.accessioned 2017-10-05T16:01:25Z
dc.date.available 2017-10-05T16:01:25Z
dc.date.issued 2006
dc.identifier 10.1074/jbc.M509483200
dc.identifier.isbn
dc.identifier.issn 00219258
dc.identifier.uri http://hdl.handle.net/10938/19503
dc.description.abstract A new variant of a group of pediatric neurodegenerative diseases known as neuronal ceroid lipofuscinosis (NCL) or Batten disease has been identified. It is termed CLN9-deficient. CLN9-deficient fibroblasts have a distinctive phenotype of rapid growth and increased apoptosis and diminished levels of ceramide, dihydroceramide, and sphingomyelin. Transfection with CLN8 but not other NCL genes corrected growth and apoptosis in CLN9-deficient cells, although the entire CLN8 sequence was normal. CLN8 is one of the TRAM-Lag1-CLN8 proteins containing a Lag1 motif. The latter imparts (dihydro)ceramide synthase activity to yeast cells. Transfection with the yeast gene Lag1 Sc and the human homolog LASS1 increased ceramide levels and partially corrected growth and apoptosis in CLN9-deficient cells. LASS2, -4, , -5, and -6 also corrected growth and apoptosis. Dihydroceramide levels and dihydroceramide synthase activity were markedly diminished in CLN9-deficient cells. Sequencing of LASS1, LASS2, LASS4, LASS5, and LASS6 genes was normal, and expression levels were increased or normal in CLN9-deficient cells by reverse transcription-PCR. N-(4-Hydroxyphenyl)retinamide (4-HPR), a dihydroceramide synthase activator, corrected growth and apoptosis and increased dihydroceramide synthase activity. Ceramide levels dropped further, and there was no increase in de novo ceramide synthesis, probably due to the effects of 4-HPR as activator of dihydroceramide synthase and inhibitor of dihydroceramide desaturase. Fumonisin B1, a dihydroceramide synthase inhibitor, exaggerated the CLN9-deficient phenotype of accelerated growth, decreased ceramide and increased apoptosis. This was neutralized by 4-HPR. We conclude that the CLN9 protein may be a regulator of dihydroceramide synthase and that 4-HPR could be developed as a treatment for CLN9-deficient patients. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
dc.format.extent
dc.format.extent Pages: (2784-2794)
dc.language English
dc.publisher BETHESDA
dc.relation.ispartof Publication Name: Journal of Biological Chemistry; Publication Year: 2006; Volume: 281; no. 5; Pages: (2784-2794);
dc.relation.ispartofseries
dc.relation.uri
dc.source Scopus
dc.subject.other
dc.title The CLN9 protein, a regulator of dihydroceramide synthase
dc.type Article
dc.contributor.affiliation Schulz, A., Duke University Medical Center, Departments of Pediatrics and Neurobiology, Durham, NC 27710, United States, University Medical Center Hamburg, D-20246 Hamburg, Germany
dc.contributor.affiliation Mousallem, T., Duke University Medical Center, Departments of Pediatrics and Neurobiology, Durham, NC 27710, United States
dc.contributor.affiliation Venkataramani, M., Duke University Medical Center, Departments of Pediatrics and Neurobiology, Durham, NC 27710, United States
dc.contributor.affiliation Persaud-Sawin, D.-A., Duke University Medical Center, Departments of Pediatrics and Neurobiology, Durham, NC 27710, United States
dc.contributor.affiliation Zucker, A., Duke University Medical Center, Departments of Pediatrics and Neurobiology, Durham, NC 27710, United States
dc.contributor.affiliation Luberto, C., Medical University of South Carolina, Department of Biochemistry, Charleston, SC 29425, United States
dc.contributor.affiliation Bielawska, A., Medical University of South Carolina, Department of Biochemistry, Charleston, SC 29425, United States
dc.contributor.affiliation Bielawski, J., Medical University of South Carolina, Department of Biochemistry, Charleston, SC 29425, United States
dc.contributor.affiliation Holthuis, J.C.M., Utrecht University, Department of Membrane Enzymology, 3584 CH Utrecht, Netherlands
dc.contributor.affiliation Jazwinski, S.M., Louisiana State University Health Sciences Center, Department of Biochemistry and Molecular Biology, New Orleans, LA 70112, United States
dc.contributor.affiliation Kozhaya, L., American University of Beirut Medical Center, Beirut, 1107-2020, Lebanon
dc.contributor.affiliation Dbaibo, G.S., American University of Beirut Medical Center, Beirut, 1107-2020, Lebanon
dc.contributor.affiliation Boustany, R.-M.N., Duke University Medical Center, Departments of Pediatrics and Neurobiology, Durham, NC 27710, United States, Depts. of Pediatrics and Neurobiology, MSRB Box 2604, Durham, NC 27710, United States
dc.contributor.authorAddress Boustany, R.-M.N.; Depts. of Pediatrics and Neurobiology, MSRB Box 2604, Durham, NC 27710, United States; email: boust001@mc.duke.edu
dc.contributor.authorCorporate University: American University of Beirut Medical Center; Faculty: Faculty of Medicine; Department: Pediatrics and Adolescent Medicine;
dc.contributor.authorDepartment Pediatrics and Adolescent Medicine
dc.contributor.authorDivision
dc.contributor.authorEmail boust001@mc.duke.edu
dc.contributor.authorFaculty Faculty of Medicine
dc.contributor.authorInitials Schulz, A
dc.contributor.authorInitials Mousallem, T
dc.contributor.authorInitials Venkataramani, M
dc.contributor.authorInitials Persaud-Sawin, DA
dc.contributor.authorInitials Zucker, A
dc.contributor.authorInitials Luberto, C
dc.contributor.authorInitials Bielawska, A
dc.contributor.authorInitials Bielawski, J
dc.contributor.authorInitials Holthuis, JCM
dc.contributor.authorInitials Jazwinski, SM
dc.contributor.authorInitials Kozhaya, L
dc.contributor.authorInitials Dbaibo, GS
dc.contributor.authorInitials Boustany, RMN
dc.contributor.authorOrcidID
dc.contributor.authorReprintAddress Boustany, RMN (reprint author), Duke Univ, Med Ctr, Dept Pediat, MSRB Box 2604, Durham, NC 27710 USA.
dc.contributor.authorResearcherID
dc.contributor.authorUniversity American University of Beirut Medical Center
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dc.description.citedCount 51
dc.description.citedTotWOSCount 51
dc.description.citedWOSCount 50
dc.format.extentCount 11
dc.identifier.articleNo
dc.identifier.coden JBCHA
dc.identifier.pubmedID 16303764
dc.identifier.scopusID 33646356745
dc.identifier.url
dc.publisher.address 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
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dc.relation.ispartofConferenceCode
dc.relation.ispartofConferenceDate
dc.relation.ispartofConferenceHosting
dc.relation.ispartofConferenceLoc
dc.relation.ispartofConferenceSponsor
dc.relation.ispartofConferenceTitle
dc.relation.ispartofFundingAgency
dc.relation.ispartOfISOAbbr J. Biol. Chem.
dc.relation.ispartOfIssue 5
dc.relation.ispartOfPart
dc.relation.ispartofPubTitle Journal of Biological Chemistry
dc.relation.ispartofPubTitleAbbr J. Biol. Chem.
dc.relation.ispartOfSpecialIssue
dc.relation.ispartOfSuppl
dc.relation.ispartOfVolume 281
dc.source.ID WOS:000234931800045
dc.type.publication Journal
dc.subject.otherAuthKeyword
dc.subject.otherChemCAS fenretinide, 65646-68-6, 75686-07-6
dc.subject.otherChemCAS fumonisin B1, 116355-83-0
dc.subject.otherChemCAS lactosylceramide, 4682-48-8
dc.subject.otherChemCAS protein, 67254-75-5
dc.subject.otherChemCAS sphingomyelin, 85187-10-6
dc.subject.otherChemCAS synthetase, 9031-56-5, 9031-57-6
dc.subject.otherChemCAS oxidoreductase, 9035-73-8, 9035-82-9, 9037-80-3, 9055-15-6
dc.subject.otherChemCAS CLN8 protein, human
dc.subject.otherChemCAS CLN9 protein, human
dc.subject.otherChemCAS Ceramides
dc.subject.otherChemCAS Fenretinide, 65646-68-6
dc.subject.otherChemCAS Fumonisins
dc.subject.otherChemCAS LAG1 protein, S cerevisiae, 156739-75-2
dc.subject.otherChemCAS LASS1 protein, human
dc.subject.otherChemCAS Membrane Proteins
dc.subject.otherChemCAS Oxidoreductases, 1.-
dc.subject.otherChemCAS Saccharomyces cerevisiae Proteins
dc.subject.otherChemCAS dihydroceramide
dc.subject.otherChemCAS dihydroceramide synthase, 1.3.-
dc.subject.otherChemCAS fumonisin B1, 116355-83-0
dc.subject.otherIndex Cells
dc.subject.otherIndex Diseases
dc.subject.otherIndex Genes
dc.subject.otherIndex Neurology
dc.subject.otherIndex Patient treatment
dc.subject.otherIndex Yeast
dc.subject.otherIndex Ceramide
dc.subject.otherIndex Dihydroceramide
dc.subject.otherIndex Dihydroceramide synthase
dc.subject.otherIndex Neurodegenerative diseases
dc.subject.otherIndex Neuronal ceroid lipofuscinosis (NCL)
dc.subject.otherIndex Sphingomyelin
dc.subject.otherIndex Proteins
dc.subject.otherIndex ceramide trihexoside
dc.subject.otherIndex dihydroceramide synthase
dc.subject.otherIndex fenretinide
dc.subject.otherIndex fumonisin B1
dc.subject.otherIndex ganglioside
dc.subject.otherIndex globoside
dc.subject.otherIndex lactosylceramide
dc.subject.otherIndex protein
dc.subject.otherIndex protein cln9
dc.subject.otherIndex sphingomyelin
dc.subject.otherIndex synthetase
dc.subject.otherIndex unclassified drug
dc.subject.otherIndex ceramide
dc.subject.otherIndex CLN8 protein, human
dc.subject.otherIndex CLN9 protein, human
dc.subject.otherIndex dihydroceramide
dc.subject.otherIndex dihydroceramide synthase
dc.subject.otherIndex fenretinide
dc.subject.otherIndex fumonisin
dc.subject.otherIndex LAG1 protein, S cerevisiae
dc.subject.otherIndex LASS1 protein, human
dc.subject.otherIndex membrane protein
dc.subject.otherIndex oxidoreductase
dc.subject.otherIndex Saccharomyces cerevisiae protein
dc.subject.otherIndex apoptosis
dc.subject.otherIndex article
dc.subject.otherIndex controlled study
dc.subject.otherIndex enzyme activity
dc.subject.otherIndex gene expression
dc.subject.otherIndex gene sequence
dc.subject.otherIndex genetic transfection
dc.subject.otherIndex human
dc.subject.otherIndex human cell
dc.subject.otherIndex neuronal ceroid lipofuscinosis
dc.subject.otherIndex priority journal
dc.subject.otherIndex reverse transcription polymerase chain reaction
dc.subject.otherIndex yeast cell
dc.subject.otherIndex cell line
dc.subject.otherIndex cell proliferation
dc.subject.otherIndex enzymology
dc.subject.otherIndex fibroblast
dc.subject.otherIndex genetics
dc.subject.otherIndex metabolism
dc.subject.otherIndex pathology
dc.subject.otherIndex physiology
dc.subject.otherIndex Apoptosis
dc.subject.otherIndex Cell Line
dc.subject.otherIndex Cell Proliferation
dc.subject.otherIndex Ceramides
dc.subject.otherIndex Fenretinide
dc.subject.otherIndex Fibroblasts
dc.subject.otherIndex Fumonisins
dc.subject.otherIndex Humans
dc.subject.otherIndex Membrane Proteins
dc.subject.otherIndex Neuronal Ceroid-Lipofuscinoses
dc.subject.otherIndex Oxidoreductases
dc.subject.otherIndex Saccharomyces cerevisiae Proteins
dc.subject.otherKeywordPlus NEURONAL CEROID-LIPOFUSCINOSIS
dc.subject.otherKeywordPlus NEUROBLASTOMA-CELL-LINES
dc.subject.otherKeywordPlus TRANSMEMBRANE PROTEIN
dc.subject.otherKeywordPlus CERAMIDE SYNTHASE
dc.subject.otherKeywordPlus MUTANT MICE
dc.subject.otherKeywordPlus FENRETINIDE
dc.subject.otherKeywordPlus MUTATIONS
dc.subject.otherKeywordPlus FAMILY
dc.subject.otherKeywordPlus N-(4-HYDROXYPHENYL)RETINAMIDE
dc.subject.otherKeywordPlus IDENTIFICATION
dc.subject.otherWOS Biochemistry and Molecular Biology


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