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The effect of histone deacetylase in...

Park, Jae Hong.

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The effect of histone deacetylase inhibition on the early events of Epstein-Barr virus reactivation.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The effect of histone deacetylase inhibition on the early events of Epstein-Barr virus reactivation./
作者:	Park, Jae Hong.
面頁冊數:	154 p.
附註:	Source: Dissertation Abstracts International, Volume: 62-10, Section: B, page: 4382.
Contained By:	Dissertation Abstracts International62-10B.
標題:	Biology, Molecular. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3031583
ISBN:	0493437495

The effect of histone deacetylase inhibition on the early events of Epstein-Barr virus reactivation.
Park, Jae Hong.

The effect of histone deacetylase inhibition on the early events of Epstein-Barr virus reactivation. - 154 p.

Source: Dissertation Abstracts International, Volume: 62-10, Section: B, page: 4382.

Thesis (Ph.D.)--Boston University, 2002.

Epstein-Barr virus (EBV)-associated diseases are often resistant to current herpesvirus chemotherapeutic agents, such as ganciclovir, because the drug target, EBV thymidine kinase (TK), is not expressed in latent infections. Histone deacetylase inhibitors (HDACIs) are known to induce EBV reactivation, although their effects are cell-type specific. It was demonstrated that EBV immediate early and early (TK) genes were induced by HDACI treatment in EBV-positive Burkitt's lymphoma lines and EBV-transformed B cell lymphoblastoid lines. The EBV latent membrane protein (LMP)-1 induces B lymphocyte immortalization, and activates constitutive signal transduction including NF-κB, JNK/p38 and JAK/STAT pathways in infected cells. During EBV latency, LMP-1 expression induces several B lymphocyte activation markers, including intercellular adhesion molecule (ICAM)-1. It was found that two structurally-distinct HDACIs, as well as phorbol ester treatment, induced homotypic aggregation in EBV-positive Burkitt's lymphoma lines. Cell surface expression of ICAM-1 was concurrently strongly induced by both HDACI and phorbol ester treatment. Among several ICAM family members, only ICAM-1 was up-regulated by both HDACI and phorbol ester treatments, suggesting that up-regulated ICAM-1 expression might mediate the observed increase in homotypic aggregation. HDACI-induced homotypic aggregation was blocked by exposure to a monoclonal antibody specific for the β-chain (CD18) of an ICAM-1 ligand, LFA-1. Surprisingly, HDAC inhibition, but not phorbol ester treatment, induced LMP-1 expression in the EBV-positive P3HR-1 cell line, and this LMP-1 species was identified by RT-PCR and immunoblot analyses as the latent form of LMP-1. Control of EBV LMP-1 gene expression by HDACI occurs at the transcriptional level, as indicated by nuclear runoff studies and analysis of steady-state mRNA levels. Dominant negative LMP-1 efficiently blocked HDACI-induced ICAM-1 up-regulation. The HDACI-induced up-regulation of ICAM-1, and homotypic aggregation, were efficiently blocked by the addition of N-acetyl-L-cysteine and by ectopic expression of a super repressor IβBα, while LMP-1 induction was unaffected, suggesting that these effects are mediated by NF-κB. We demonstrated, therefore, that the latent isoform of LMP-1 is induced by HDAC inhibition, and that HDACI-induced latent LMP-1 expression via an NF-κB-dependent mechanism is responsible for ICAM-1 expression up-regulation. These activities can be used to improve the therapeutic application of histone deacetylase inhibitors.

ISBN: 0493437495Subjects--Topical Terms:

1017719
Biology, Molecular.

The effect of histone deacetylase inhibition on the early events of Epstein-Barr virus reactivation.
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