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Article: Krüppel-like factor 15 activates hepatitis B virus gene expression and replication

TitleKrüppel-like factor 15 activates hepatitis B virus gene expression and replication
Other TitlesKLF15 activates hepatitis B virus gene expression and replication
Authors
Issue Date2011
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/
AbstractHepatitis B virus (HBV) is a small DNA virus that requires cellular transcription factors for the expression of its genes. To understand the molecular mechanisms that regulate HBV gene expression, we conducted a yeast one-hybrid screen to identify novel cellular transcription factors that may control HBV gene expression. Here, we demonstrate that Kruppel-like factor 15 (KLF15), a liver-enriched transcription factor, can robustly activate HBV surface and core promoters. Mutations in the putative KLF15 binding site in the HBV core promoter abolished the ability of KLF15 to activate the core promoter in luciferase assays. Furthermore, the overexpression of KLF15 stimulated the expression of HBV surface antigen (HBsAg) and the core protein and enhanced viral replication. Conversely, small interfering RNA knockdown of the endogenous KLF15 in Huh7 cells resulted in a reduction in HBV surface- and core-promoter activities. In electrophoretic mobility shift and chromatin immunoprecipitation assays, KLF15 binds to DNA probes derived from the core promoter and the surface promoter. Introduction of an expression vector for KLF15 short hairpin RNA, together with the HBV genome into the mouse liver using hydrodynamic injection, resulted in a significant reduction in viral gene expression and DNA replication. Additionally, mutations in the KLF15 response element in the HBV core promoter significantly reduced viral DNA levels in the mouse serum. CONCLUSION: KLF15 is a novel transcriptional activator for HBV core and surface promoters. It is possible that KLF15 may serve as a potential therapeutic target to reduce HBV gene expression and viral replication.
Persistent Identifierhttp://hdl.handle.net/10722/139514
ISSN
2015 Impact Factor: 11.711
2015 SCImago Journal Rankings: 4.752
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
National Institutes of HealthR01CA55578
R21RR024229
P01CA123328
American Cancer Society
Funding Information:

This work was supported by National Institutes of Health grants R01CA55578 (to T.S.B.Y), R21RR024229 (to T.S.B.Y), and P01CA123328 (to T.S.B.Y and J.H.J.O.), a VA Merit Review Award (to T.S.B.Y), and an American Cancer Society postdoctoral fellowship (to T.T.).

 

DC FieldValueLanguage
dc.contributor.authorZhou, Jen_HK
dc.contributor.authorTan, Ten_HK
dc.contributor.authorTian, Yen_HK
dc.contributor.authorZheng, Ben_HK
dc.contributor.authorOu, JHen_HK
dc.contributor.authorHuang, EJen_HK
dc.contributor.authorYen, TSBen_HK
dc.date.accessioned2011-09-23T05:50:58Z-
dc.date.available2011-09-23T05:50:58Z-
dc.date.issued2011en_HK
dc.identifier.issn0270-9139en_HK
dc.identifier.urihttp://hdl.handle.net/10722/139514-
dc.description.abstractHepatitis B virus (HBV) is a small DNA virus that requires cellular transcription factors for the expression of its genes. To understand the molecular mechanisms that regulate HBV gene expression, we conducted a yeast one-hybrid screen to identify novel cellular transcription factors that may control HBV gene expression. Here, we demonstrate that Kruppel-like factor 15 (KLF15), a liver-enriched transcription factor, can robustly activate HBV surface and core promoters. Mutations in the putative KLF15 binding site in the HBV core promoter abolished the ability of KLF15 to activate the core promoter in luciferase assays. Furthermore, the overexpression of KLF15 stimulated the expression of HBV surface antigen (HBsAg) and the core protein and enhanced viral replication. Conversely, small interfering RNA knockdown of the endogenous KLF15 in Huh7 cells resulted in a reduction in HBV surface- and core-promoter activities. In electrophoretic mobility shift and chromatin immunoprecipitation assays, KLF15 binds to DNA probes derived from the core promoter and the surface promoter. Introduction of an expression vector for KLF15 short hairpin RNA, together with the HBV genome into the mouse liver using hydrodynamic injection, resulted in a significant reduction in viral gene expression and DNA replication. Additionally, mutations in the KLF15 response element in the HBV core promoter significantly reduced viral DNA levels in the mouse serum. CONCLUSION: KLF15 is a novel transcriptional activator for HBV core and surface promoters. It is possible that KLF15 may serve as a potential therapeutic target to reduce HBV gene expression and viral replication.en_HK
dc.languageengen_US
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/en_HK
dc.relation.ispartofHepatologyen_HK
dc.rightsHepatology. Copyright © John Wiley & Sons, Inc.en_US
dc.subject.meshDNA-Binding Proteins - drug effects - genetics - physiologyen_HK
dc.subject.meshGene Expression Regulation, Viral - drug effects - physiologyen_HK
dc.subject.meshHepatitis B virus - genetics - physiologyen_HK
dc.subject.meshKruppel-Like Transcription Factors - drug effects - genetics - physiologyen_HK
dc.subject.meshNuclear Proteins - drug effects - genetics - physiologyen_HK
dc.titleKrüppel-like factor 15 activates hepatitis B virus gene expression and replicationen_HK
dc.title.alternativeKLF15 activates hepatitis B virus gene expression and replication-
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0270-9139&volume=54&issue=1&spage=109&epage=121&date=2011&atitle=Krüppel-like+factor+15+activates+hepatitis+B+virus+gene+expression+and+replicationen_US
dc.identifier.emailZhou, J: jiezhou@hku.hken_HK
dc.identifier.emailZheng, B: bzheng@hkucc.hku.hken_HK
dc.identifier.emailHuang, EJ: eric.huang2@ucsf.edu-
dc.identifier.authorityZhou, J=rp01412en_HK
dc.identifier.authorityZheng, B=rp00353en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1002/hep.24362en_HK
dc.identifier.pmid21503941-
dc.identifier.pmcidPMC3125411-
dc.identifier.scopuseid_2-s2.0-79959562500en_HK
dc.identifier.hkuros192819en_US
dc.identifier.volume54en_HK
dc.identifier.issue1en_HK
dc.identifier.spage109en_HK
dc.identifier.epage121en_HK
dc.identifier.isiWOS:000292440700016-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridYen, TB=7202232733en_HK
dc.identifier.scopusauthoridHuang, EJ=8048570300en_HK
dc.identifier.scopusauthoridJames Ou, JH=36118771400en_HK
dc.identifier.scopusauthoridZheng, B=7201780588en_HK
dc.identifier.scopusauthoridTian, Y=7402840414en_HK
dc.identifier.scopusauthoridTan, T=7402021210en_HK
dc.identifier.scopusauthoridZhou, J=7405550443en_HK

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