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Regulation of stress associated prot...
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Gillis, Peter A.
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Regulation of stress associated protein kinase signaling pathways and apoptosis by herpes simplex virus type 1 infected cell protein 27.
Record Type:
Language materials, printed : Monograph/item
Title/Author:
Regulation of stress associated protein kinase signaling pathways and apoptosis by herpes simplex virus type 1 infected cell protein 27./
Author:
Gillis, Peter A.
Description:
193 p.
Notes:
Source: Dissertation Abstracts International, Volume: 71-03, Section: B, page: 1548.
Contained By:
Dissertation Abstracts International71-03B.
Subject:
Biology, Molecular. -
Online resource:
http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3396928
ISBN:
9781109666168
Regulation of stress associated protein kinase signaling pathways and apoptosis by herpes simplex virus type 1 infected cell protein 27.
Gillis, Peter A.
Regulation of stress associated protein kinase signaling pathways and apoptosis by herpes simplex virus type 1 infected cell protein 27.
- 193 p.
Source: Dissertation Abstracts International, Volume: 71-03, Section: B, page: 1548.
Thesis (Ph.D.)--University of Minnesota, 2010.
Infected cell protein 27 (ICP27) is an immediate early (IE) herpes simplex virus type 1 (HSV-1) regulatory protein. During the course of a HSV-1 infection, ICP27 has been implicated in a variety of functions important for viral replication including host shut-off, viral gene expression, stress activated protein kinase (SAPK) activation, and apoptosis inhibition. However, many of these studies have relied on infections with viral deletion mutants to make these observations, but have failed to separate the direct and indirect effects of ICP27 on viral replication and cellular function.
ISBN: 9781109666168Subjects--Topical Terms:
1017719
Biology, Molecular.
Regulation of stress associated protein kinase signaling pathways and apoptosis by herpes simplex virus type 1 infected cell protein 27.
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193 p.
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Source: Dissertation Abstracts International, Volume: 71-03, Section: B, page: 1548.
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Adviser: Stephen A. Rice.
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Thesis (Ph.D.)--University of Minnesota, 2010.
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Infected cell protein 27 (ICP27) is an immediate early (IE) herpes simplex virus type 1 (HSV-1) regulatory protein. During the course of a HSV-1 infection, ICP27 has been implicated in a variety of functions important for viral replication including host shut-off, viral gene expression, stress activated protein kinase (SAPK) activation, and apoptosis inhibition. However, many of these studies have relied on infections with viral deletion mutants to make these observations, but have failed to separate the direct and indirect effects of ICP27 on viral replication and cellular function.
520
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To examine the direct functions of ICP27, we engineered stable HeLa cell lines that inducibly express ICP27. We showed that ICP27 expression is sufficient to activate p38 signaling to a level similar to that which is observed during wild type HSV-1 infection. Interestingly, ICP27 expression is only able to induce a modest level of JNK signaling, compared to the high levels observed during WT HSV-1 infection. Using chemical inhibitors, we show that the ICP27-mediated activation of p38 signaling triggers apoptosis in the inducible cell lines demonstrating that ICP27 is a pro-apoptotic factor. However, it is likely that additional downstream ICP27-dependent viral factors inhibit apoptosis during HSV-1 infection.
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In an effort to better understand the regulation of apoptosis ICP27, we wanted to determine the effects of ICP27 expression on NF-kappaB activation. During HSV-1 infection ICP27-mediated JNK signaling is required for the activation of NF-kappaB, which is required for the inhibition of apoptosis. Using our inducible cell lines, we found that ICP27 expression alone is unable to activate NF-kappaB, suggesting that at least one additional ICP27-dependent viral factor is required. We demonstrate that the HSV-1 protein UL37 is expressed in an ICP27/JNK signaling-dependent manner and is capable of activating NF-kappaB. Furthermore, expression of UL37 in an ICP27-independent fashion is able to delay apoptosis induced by infection with an ICP27 null mutant.
520
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Finally, we wanted to characterize the effects of ICP27-mediated p38 signaling on normal cellular function. Using the inducible cell lines, we demonstrate that ICP27 and subsequent p38 signaling are capable of stabilizing the ARE-containing IEX-1 transcript in the absence of infection, by manipulating cellular pathways regulating mRNA decay. During the course of these studies, we also observed that ICP27 expression activates elements of the cellular integrated stress response and the endoplasmic reticulum stress pathways leading to eIF2alpha phosphorylation and IRE1 activation, respectively. The cellular response to ER stress induced by ICP27 could provide a mechanism for induction of SAPK signaling. These combined results indicate that ICP27 functions as an important regulator of cell fate during HSV-1 infection.
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School code: 0130.
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Biology, Molecular.
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Biology, Cell.
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Biology, Virology.
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Dunny, Gary M.
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committee member
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Conklin, Kathleen F.
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committee member
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http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3396928
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