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A novel mechanism underlying BCL-2 a...

Zimmermann, Angela K.

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A novel mechanism underlying BCL-2 antioxidant function: Its role in mitochondrial apoptotic pathways and virus-induced neuronal cell death.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	A novel mechanism underlying BCL-2 antioxidant function: Its role in mitochondrial apoptotic pathways and virus-induced neuronal cell death./
Author:	Zimmermann, Angela K.
Description:	162 p.
Notes:	Adviser: Kenneth L. Tyler.
Contained By:	Dissertation Abstracts International68-08B.
Subject:	Biology, Cell. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3277188
ISBN:	9780549190455

A novel mechanism underlying BCL-2 antioxidant function: Its role in mitochondrial apoptotic pathways and virus-induced neuronal cell death.
Zimmermann, Angela K.

A novel mechanism underlying BCL-2 antioxidant function: Its role in mitochondrial apoptotic pathways and virus-induced neuronal cell death. - 162 p.

Adviser: Kenneth L. Tyler.

Thesis (Ph.D.)--University of Colorado Health Sciences Center, 2007.

Bcl-2 is a pro-survival protein which regulates the intrinsic mitochondrial pathway of apoptosis. Disruption of Bcl-2 function has profound consequences on the mitochondria and the cell, triggering activation of mitochondrial-associated cell death pathways (intrinsic apoptosis). Here, we investigate the effect of Bcl-2 loss-of-function on neuronal survival. When Bcl-2 is inactivated via antisensemediated downregulation or BH3 domain binding in the hydrophobic groove (BH3 groove), its antioxidant-like function is disrupted and neurons succumb to apoptosis. Addition of cell permeable antioxidants completely block this oxidative stress-dependent death. We report here that Bcl-2 loss of antioxidant function induced by addition of small molecule BH3 domain mimetics is likely due to disruption of a critical and previously unknown glutathione binding property of Bcl-2 mediated by the BH3 groove. In addition, this novel interaction regulates the uptake of GSH into the mitochondria which is essential to protect the organelle from incurring oxidative damage. Alternatively, when Bcl-2 function is inhibited by phosphorylation, as occurs when specific cellular kinases are activated in reovirus infection, the addition of antioxidants has no effect on neuronal survival. In an effort to determine whether phosphorylation of Bcl-2 inhibits its anti-apoptotic function, we analyzed the protective capacity of a panel of Bcl-2 phosphorylation mutants. Overexpression of a phosphorylation-mimic Bcl-2 mutant confirms that although its antioxidant-like function appears to remain intact, its capacity to protect against reovirus-induced apoptosis is abolished. This phosphorylation mimic Bcl-2 mutant exhibits decreased binding of pro-apoptotic Bax, suggesting a potential mechanism through which reovirus inhibits Bcl-2 and initiates apoptosis. Bcl-2 anti-apoptotic function mediates neuronal survival and understanding how its activity is disrupted in apoptosis could potentially facilitate neurodegenerative disease research. The form and content of this abstract are approved.

ISBN: 9780549190455Subjects--Topical Terms:

1017686
Biology, Cell.

A novel mechanism underlying BCL-2 antioxidant function: Its role in mitochondrial apoptotic pathways and virus-induced neuronal cell death.
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020 $a 9780549190455
035 $a (UMI)AAI3277188
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100 1 $a Zimmermann, Angela K. $3 1267726
245 1 2 $a A novel mechanism underlying BCL-2 antioxidant function: Its role in mitochondrial apoptotic pathways and virus-induced neuronal cell death.
300 $a 162 p.
500 $a Adviser: Kenneth L. Tyler.
500 $a Source: Dissertation Abstracts International, Volume: 68-08, Section: B, page: 5045.
502 $a Thesis (Ph.D.)--University of Colorado Health Sciences Center, 2007.
520 $a Bcl-2 is a pro-survival protein which regulates the intrinsic mitochondrial pathway of apoptosis. Disruption of Bcl-2 function has profound consequences on the mitochondria and the cell, triggering activation of mitochondrial-associated cell death pathways (intrinsic apoptosis). Here, we investigate the effect of Bcl-2 loss-of-function on neuronal survival. When Bcl-2 is inactivated via antisensemediated downregulation or BH3 domain binding in the hydrophobic groove (BH3 groove), its antioxidant-like function is disrupted and neurons succumb to apoptosis. Addition of cell permeable antioxidants completely block this oxidative stress-dependent death. We report here that Bcl-2 loss of antioxidant function induced by addition of small molecule BH3 domain mimetics is likely due to disruption of a critical and previously unknown glutathione binding property of Bcl-2 mediated by the BH3 groove. In addition, this novel interaction regulates the uptake of GSH into the mitochondria which is essential to protect the organelle from incurring oxidative damage. Alternatively, when Bcl-2 function is inhibited by phosphorylation, as occurs when specific cellular kinases are activated in reovirus infection, the addition of antioxidants has no effect on neuronal survival. In an effort to determine whether phosphorylation of Bcl-2 inhibits its anti-apoptotic function, we analyzed the protective capacity of a panel of Bcl-2 phosphorylation mutants. Overexpression of a phosphorylation-mimic Bcl-2 mutant confirms that although its antioxidant-like function appears to remain intact, its capacity to protect against reovirus-induced apoptosis is abolished. This phosphorylation mimic Bcl-2 mutant exhibits decreased binding of pro-apoptotic Bax, suggesting a potential mechanism through which reovirus inhibits Bcl-2 and initiates apoptosis. Bcl-2 anti-apoptotic function mediates neuronal survival and understanding how its activity is disrupted in apoptosis could potentially facilitate neurodegenerative disease research. The form and content of this abstract are approved.
590 $a School code: 0831.
650 4 $a Biology, Cell. $3 1017686
650 4 $a Biology, Neuroscience. $3 1017680
650 4 $a Biology, Virology. $3 1019068
690 $a 0317
690 $a 0379
690 $a 0720
710 2 $a University of Colorado Health Sciences Center. $3 1023815
773 0 $t Dissertation Abstracts International $g 68-08B.
790 $a 0831
790 1 0 $a Tyler, Kenneth L., $e advisor
791 $a Ph.D.
792 $a 2007
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3277188