Find results with:

Add another field

Search by date

to

Searching collections:

Dartmouth Dissertations

Add or remove collections

Home Dartmouth Dissertations ganju2002 1

Reference URL

To link to the entire object, paste this link in email, IM or document

To embed the entire object, paste this HTML in website

To link to this page, paste this link in email, IM or document

To embed this page, paste this HTML in website

Bcl-2 family proteins and the regulation of apoptosis.

you wish to report:

Your comment:

Your Name:

Submit

Cancel

...

Back to top

Powered by CONTENTdm®

Call No.	QH671 .G36 2002
Author	Ganju, Neema
Title	Bcl-2 family proteins and the regulation of apoptosis.
Date	2002
Abstract	Apoptosis is induced by chemicals and death receptor activation. Although the stimuli are different, common proteins are activated downstream. The Bcl-2 family of proteins plays an important role in mediating apoptotic signaling at the mitochondria resulting in cytochrome c release and apoptosis. These proteins can be divided into three categories: anti-apoptotic (Bcl-X L , Bcl-2), pro-apoptotic (Bax, Bak), and BH3-only (Bid, Bim). The BH3-only proteins are hypothesized to assist in the activation of pro-apoptotic proteins. This thesis focused on the interplay between these proteins and their impact on apoptois. It was concluded that BH3-only proteins are likely activated specifically depending on apoptotic insult and that these proteins are the key mediators in the activation of pro-apoptotic Bcl-2 proteins. Chemical inhibitors and over-expression systems were used to investigate the temporal activation of BH3-only proteins and subsequently the pro-apoptotic Bcl-2 family members. In both chemical and receptor apoptosis, the protein phosphatase inhibitor calyculin A prevented Bax translocation and the subsequent markers of apoptosis. Caspase inhibition by z-VAD-fmk showed caspase 8 and Bid cleavage are required for Bax translocation in the receptor pathway, but not in the chemical pathway. Therefore, Bax activation is not dependent on Bid in the chemical pathway. Over-expression of Bcl-X L prevented Bax translocation presumably because there is insufficient BH3-only protein to inhibit over-expressed Bcl-X L. Zinc inhibited apoptosis at the level of Bax and Bak oligomerization in the chemical pathway, but not in the receptor pathway, indicating that Bid activation is not sensitive to inhibition by zinc. Finally, Bax translocation was inhibited by taxol in the chemical but not the receptor pathway, suggesting that activation of the BH3-only protein required for Bax translocation in the chemical pathway is inhibited by taxol. The above conclusions establish the importance of BH3-only proteins in both pathways of apoptosis. They confirm that in the receptor pathway of apoptosis Bid is the primary BH3-only protein mediating the activation of Bax and Bak, while Bid plays no role in Bax and Bak activation in the chemical pathway. Using chemical modulators of signaling, zinc was established to be important in inhibiting the chemical pathway, but not the receptor pathway, while calyculin A inhibited both pathways effectively. This establishes that zinc may be mediating its effects on a specific BH3-only protein, while calyculin A is targeting a protein phosphorylation that presumably impacts different phosphoproteins in each pathway. In summary, these results establish a temporal relationship for several apoptotic proteins including members of the Bcl-2 family and mechanisms for their regulation that may be suitable pharmacologic targets to combat diseases in which apoptosis plays a key role.
Description	1 online resource (xiii, 127 leaves) : illustrations
Format	application/pdf
Advisor	Eastman, Alan
Subject	Apoptosis. ; Proteins. ; Cellular signal transduction. ; Proto-Oncogene Proteins c-bcl-2.
College	Dartmouth Medical School -- Department of Pharmacology and Toxicology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D)--Dartmouth College.
Copyright	In Copyright. This material is protected by copyright and/or related rights. You are free to use this material in any way that is permitted by copyright law that applies to your use. For other uses, you need to obtain permission from the rights-holder(s). http://rightsstatements.org/page/InC/1.0/
DOI	https://doi.org10.1349/ddlp.2736

Title	ganju2002 1
Full Text	Bcl-2 Family Proteins and the Regulation of Apoptosis A Thesis Submitted to the Faculty in Partial Fulfillment of the Requirements for the Degree Of Doctor Of Philosophy in Pharmacology And Toxicology by Neema Ganju DARTMOUTH COLLEGE Hanover, New Hampshire December 3,2002 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

	All
	Pages Enter page numbers or page ranges separated by commas. For example: 1,3,5-12

Find results with:

Searching collections:

Home Dartmouth Dissertations ganju2002 1

Bcl-2 family proteins and the regulation of apoptosis.

ganju2002 1

Object Description

Description

Bcl-2 family proteins and the regulation of apoptosis.

Bcl-2 family proteins and the regulation of apoptosis.