The role of helioxanthin in inhibiting human hepatitis B viral replication and gene expression by in

[Guest guest]

The role of helioxanthin in inhibiting human hepatitis B viral replication and

gene expression by interfering with the host transcriptional machinery of viral

promoters

Ya Ping Tsenga, Yueh Hsiung Kuob, c, Cheng-Po Hud, e, King-Song Jengf, Damodar

Janmanchia, Chih Hsiu Ling, Chen Kung Chouh, , and Sheau Farn Yeha, ,

aInstitute of Biochemistry and Molecular Biology, National Yang-Ming University,

Taipei, Taiwan, ROC

bTsuzuki Institute for Traditional Medicine, College of Pharmacy, China Medical

University, Taichung, Taiwan, ROC

cAgricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan,

ROC

dDepartment of Life Science, Tunghai University, Taichung, Taiwan, ROC

eDepartment of Medical Research and Education, Taipei Veterans General Hospital,

Taipei, Taiwan, ROC

fInstitute of Molecular Biology, Academia Sinica, Taipei, Taiwan, ROC

gInstitute of Chemistry, Academia Sinica, Taipei, Taiwan, ROC

hDepartment of Life Science, Chang Gung University, Tao-Yuan, Taiwan, ROC

Received 24 August 2007; revised 22 November 2007; accepted 21 December 2007.

Available online 18 January 2008.

Abstract

A non-nucleosidic compound, Helioxanthin (HE-145), was found to suppress HBV

gene expression and replication in HCC cells. To understand the molecular mode

of action of HE-145 on HBV gene expression, the effects of HE-145 on four viral

promoter activities using luciferase as a reporter were examined. It was found

that HE-145 selectively suppresses surface antigen promoter II (SPII) and core

promoter (CP) but has no effect on surface antigen promoter I (SPI) or promoter

for X gene (Xp). The suppressive effects of HE-145 on either SPII or CP activity

is liver-specific, since no suppressive activity of HE-145 was observed when CP

or SPII promoter activity was assayed in non-liver cells such as HeLa or 293T.

To examine the mode of action of HE-145, EMSA analysis revealed that HE-145

decreased the DNA-binding activity of nuclear extract of HepA2 cells to specific

cis element of HBV promoter for core antigen, including peroxisome

proliferator-activated receptors (PPARs), PPARs binding site (PPRE),

á-fetoprotein transcription factor (FTF), and Sp1. Ectopic expression of PPARã

or HNF4á partially reversed the HE-145-mediated suppression of HBV RNA.

Therefore, HE-145 may represent a novel class of anti-HBV agents which

selectively modulate transcriptional machinery of human liver cells to suppress

HBV gene expression and replication.

Corresponding author.

Corresponding author. Tel.: +886 2 2826 7117; fax: +886 2 2826 4843.

Antiviral Research

Volume 77, Issue 3, March 2008, Pages 206-214

http://www.sciencedirect.com/science?_ob=ArticleURL & _udi=B6T2H-4RM881F-1 & _user=1\

0 & _coverDate=03%2F31%2F2008 & _rdoc=6 & _fmt=summary & _orig=browse & _srch=doc-info(%23\

toc%234919%232008%23999229996%23679845%23FLA%23display%23Volume) & _cdi=4919 & _sort\

=d & _docanchor= & _ct=11 & _acct=C000050221 & _version=1 & _urlVersion=0 & _userid=10 & md5=c\

997d604d7fbbc985895d2c5077424a6

_________________________________________________________________

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[Guest guest]

The role of helioxanthin in inhibiting human hepatitis B viral replication and

gene expression by interfering with the host transcriptional machinery of viral

promoters

Ya Ping Tsenga, Yueh Hsiung Kuob, c, Cheng-Po Hud, e, King-Song Jengf, Damodar

Janmanchia, Chih Hsiu Ling, Chen Kung Chouh, , and Sheau Farn Yeha, ,

aInstitute of Biochemistry and Molecular Biology, National Yang-Ming University,

Taipei, Taiwan, ROC

bTsuzuki Institute for Traditional Medicine, College of Pharmacy, China Medical

University, Taichung, Taiwan, ROC

cAgricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan,

ROC

dDepartment of Life Science, Tunghai University, Taichung, Taiwan, ROC

eDepartment of Medical Research and Education, Taipei Veterans General Hospital,

Taipei, Taiwan, ROC

fInstitute of Molecular Biology, Academia Sinica, Taipei, Taiwan, ROC

gInstitute of Chemistry, Academia Sinica, Taipei, Taiwan, ROC

hDepartment of Life Science, Chang Gung University, Tao-Yuan, Taiwan, ROC

Received 24 August 2007; revised 22 November 2007; accepted 21 December 2007.

Available online 18 January 2008.

Abstract

A non-nucleosidic compound, Helioxanthin (HE-145), was found to suppress HBV

gene expression and replication in HCC cells. To understand the molecular mode

of action of HE-145 on HBV gene expression, the effects of HE-145 on four viral

promoter activities using luciferase as a reporter were examined. It was found

that HE-145 selectively suppresses surface antigen promoter II (SPII) and core

promoter (CP) but has no effect on surface antigen promoter I (SPI) or promoter

for X gene (Xp). The suppressive effects of HE-145 on either SPII or CP activity

is liver-specific, since no suppressive activity of HE-145 was observed when CP

or SPII promoter activity was assayed in non-liver cells such as HeLa or 293T.

To examine the mode of action of HE-145, EMSA analysis revealed that HE-145

decreased the DNA-binding activity of nuclear extract of HepA2 cells to specific

cis element of HBV promoter for core antigen, including peroxisome

proliferator-activated receptors (PPARs), PPARs binding site (PPRE),

á-fetoprotein transcription factor (FTF), and Sp1. Ectopic expression of PPARã

or HNF4á partially reversed the HE-145-mediated suppression of HBV RNA.

Therefore, HE-145 may represent a novel class of anti-HBV agents which

selectively modulate transcriptional machinery of human liver cells to suppress

HBV gene expression and replication.

Corresponding author.

Corresponding author. Tel.: +886 2 2826 7117; fax: +886 2 2826 4843.

Antiviral Research

Volume 77, Issue 3, March 2008, Pages 206-214

http://www.sciencedirect.com/science?_ob=ArticleURL & _udi=B6T2H-4RM881F-1 & _user=1\

0 & _coverDate=03%2F31%2F2008 & _rdoc=6 & _fmt=summary & _orig=browse & _srch=doc-info(%23\

toc%234919%232008%23999229996%23679845%23FLA%23display%23Volume) & _cdi=4919 & _sort\

=d & _docanchor= & _ct=11 & _acct=C000050221 & _version=1 & _urlVersion=0 & _userid=10 & md5=c\

997d604d7fbbc985895d2c5077424a6

_________________________________________________________________

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[Guest guest]

The role of helioxanthin in inhibiting human hepatitis B viral replication and

gene expression by interfering with the host transcriptional machinery of viral

promoters

Ya Ping Tsenga, Yueh Hsiung Kuob, c, Cheng-Po Hud, e, King-Song Jengf, Damodar

Janmanchia, Chih Hsiu Ling, Chen Kung Chouh, , and Sheau Farn Yeha, ,

aInstitute of Biochemistry and Molecular Biology, National Yang-Ming University,

Taipei, Taiwan, ROC

bTsuzuki Institute for Traditional Medicine, College of Pharmacy, China Medical

University, Taichung, Taiwan, ROC

cAgricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan,

ROC

dDepartment of Life Science, Tunghai University, Taichung, Taiwan, ROC

eDepartment of Medical Research and Education, Taipei Veterans General Hospital,

Taipei, Taiwan, ROC

fInstitute of Molecular Biology, Academia Sinica, Taipei, Taiwan, ROC

gInstitute of Chemistry, Academia Sinica, Taipei, Taiwan, ROC

hDepartment of Life Science, Chang Gung University, Tao-Yuan, Taiwan, ROC

Received 24 August 2007; revised 22 November 2007; accepted 21 December 2007.

Available online 18 January 2008.

Abstract

A non-nucleosidic compound, Helioxanthin (HE-145), was found to suppress HBV

gene expression and replication in HCC cells. To understand the molecular mode

of action of HE-145 on HBV gene expression, the effects of HE-145 on four viral

promoter activities using luciferase as a reporter were examined. It was found

that HE-145 selectively suppresses surface antigen promoter II (SPII) and core

promoter (CP) but has no effect on surface antigen promoter I (SPI) or promoter

for X gene (Xp). The suppressive effects of HE-145 on either SPII or CP activity

is liver-specific, since no suppressive activity of HE-145 was observed when CP

or SPII promoter activity was assayed in non-liver cells such as HeLa or 293T.

To examine the mode of action of HE-145, EMSA analysis revealed that HE-145

decreased the DNA-binding activity of nuclear extract of HepA2 cells to specific

cis element of HBV promoter for core antigen, including peroxisome

proliferator-activated receptors (PPARs), PPARs binding site (PPRE),

á-fetoprotein transcription factor (FTF), and Sp1. Ectopic expression of PPARã

or HNF4á partially reversed the HE-145-mediated suppression of HBV RNA.

Therefore, HE-145 may represent a novel class of anti-HBV agents which

selectively modulate transcriptional machinery of human liver cells to suppress

HBV gene expression and replication.

Corresponding author.

Corresponding author. Tel.: +886 2 2826 7117; fax: +886 2 2826 4843.

Antiviral Research

Volume 77, Issue 3, March 2008, Pages 206-214

http://www.sciencedirect.com/science?_ob=ArticleURL & _udi=B6T2H-4RM881F-1 & _user=1\

0 & _coverDate=03%2F31%2F2008 & _rdoc=6 & _fmt=summary & _orig=browse & _srch=doc-info(%23\

toc%234919%232008%23999229996%23679845%23FLA%23display%23Volume) & _cdi=4919 & _sort\

=d & _docanchor= & _ct=11 & _acct=C000050221 & _version=1 & _urlVersion=0 & _userid=10 & md5=c\

997d604d7fbbc985895d2c5077424a6

_________________________________________________________________

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power.

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[Guest guest]

The role of helioxanthin in inhibiting human hepatitis B viral replication and

gene expression by interfering with the host transcriptional machinery of viral

promoters

Ya Ping Tsenga, Yueh Hsiung Kuob, c, Cheng-Po Hud, e, King-Song Jengf, Damodar

Janmanchia, Chih Hsiu Ling, Chen Kung Chouh, , and Sheau Farn Yeha, ,

aInstitute of Biochemistry and Molecular Biology, National Yang-Ming University,

Taipei, Taiwan, ROC

bTsuzuki Institute for Traditional Medicine, College of Pharmacy, China Medical

University, Taichung, Taiwan, ROC

cAgricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan,

ROC

dDepartment of Life Science, Tunghai University, Taichung, Taiwan, ROC

eDepartment of Medical Research and Education, Taipei Veterans General Hospital,

Taipei, Taiwan, ROC

fInstitute of Molecular Biology, Academia Sinica, Taipei, Taiwan, ROC

gInstitute of Chemistry, Academia Sinica, Taipei, Taiwan, ROC

hDepartment of Life Science, Chang Gung University, Tao-Yuan, Taiwan, ROC

Received 24 August 2007; revised 22 November 2007; accepted 21 December 2007.

Available online 18 January 2008.

Abstract

A non-nucleosidic compound, Helioxanthin (HE-145), was found to suppress HBV

gene expression and replication in HCC cells. To understand the molecular mode

of action of HE-145 on HBV gene expression, the effects of HE-145 on four viral

promoter activities using luciferase as a reporter were examined. It was found

that HE-145 selectively suppresses surface antigen promoter II (SPII) and core

promoter (CP) but has no effect on surface antigen promoter I (SPI) or promoter

for X gene (Xp). The suppressive effects of HE-145 on either SPII or CP activity

is liver-specific, since no suppressive activity of HE-145 was observed when CP

or SPII promoter activity was assayed in non-liver cells such as HeLa or 293T.

To examine the mode of action of HE-145, EMSA analysis revealed that HE-145

decreased the DNA-binding activity of nuclear extract of HepA2 cells to specific

cis element of HBV promoter for core antigen, including peroxisome

proliferator-activated receptors (PPARs), PPARs binding site (PPRE),

á-fetoprotein transcription factor (FTF), and Sp1. Ectopic expression of PPARã

or HNF4á partially reversed the HE-145-mediated suppression of HBV RNA.

Therefore, HE-145 may represent a novel class of anti-HBV agents which

selectively modulate transcriptional machinery of human liver cells to suppress

HBV gene expression and replication.

Corresponding author.

Corresponding author. Tel.: +886 2 2826 7117; fax: +886 2 2826 4843.

Antiviral Research

Volume 77, Issue 3, March 2008, Pages 206-214

http://www.sciencedirect.com/science?_ob=ArticleURL & _udi=B6T2H-4RM881F-1 & _user=1\

0 & _coverDate=03%2F31%2F2008 & _rdoc=6 & _fmt=summary & _orig=browse & _srch=doc-info(%23\

toc%234919%232008%23999229996%23679845%23FLA%23display%23Volume) & _cdi=4919 & _sort\

=d & _docanchor= & _ct=11 & _acct=C000050221 & _version=1 & _urlVersion=0 & _userid=10 & md5=c\

997d604d7fbbc985895d2c5077424a6

_________________________________________________________________

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power.

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