Skip Navigation



ToxSci Advance Access published online on March 30, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm071
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow All Versions of this Article:
98/1/125    most recent
kfm071v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Schlezinger, J. J.
Right arrow Articles by Sherr, D. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schlezinger, J. J.
Right arrow Articles by Sherr, D. H.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

An L-tyrosine Derivative and PPAR{gamma} Agonist, GW7845, Activates a Multi-Faceted Caspase Cascade in Bone Marrow B Cells

Jennifer J. Schlezinger*, Jessica K. Emberley{dagger}, Stephanie L. Bissonnette* and David H. Sherr*

* Department of Environmental Health, Boston University School of Public Health {dagger} Department of Microbiology, Boston University School of Medicine, Boston, MA, 02118, USA

Correspondence to: Jennifer J. Schlezinger, Ph.D., Boston University School of Public Health, Dept. of Environmental Health, 715 Albany Street, R-405, Boston, MA 02118, Telephone: 617-638-6461, Fax: 617-638-6463, Email: jschlezi{at}bu.edu

Received January 17, 2007; revision received March 23, 2007; accepted March 23, 2007


  Abstract

Apoptosis is a critical event in the deletion of B lymphocytes prior to their migration to the periphery. Synthetic PPAR{gamma} agonists, including the drug GW7845 and the environmental contaminant mono-(2-ethylhexyl) phthalate, as well as an endogenous ligand, 15-deoxy-{Delta}12,14-prostaglandin J2, induce clonally unrestricted apoptosis in pro/pre-B cells. Considering that PPAR{gamma} agonists are used clinically for the treatment of diabetes and postulated to be useful as chemotherapeutics, we used GW7845 as a model PPAR{gamma} agonist to examine the mechanism of cell death that may contribute to tumor killing as well as normal bone marrow B lymphocyte toxicity. GW7845 induced rapid mitochondrial membrane depolarization and release of cytochrome c, along with nearly concurrent activation of capases-2, -3, -8 and -9 in primary pro-B cells and BU-11 cells, a non-transformed pro/pre-B cell line. GW7845-induced apoptosis was reduced significantly in Bax deficient and Apaf-1 mutant primary pro-B cells, supporting the conclusion that GW7845-induced apoptosis is mitochondria- and apoptosome-dependent. Using VAD-FMK as a pan-caspase inhibitor, we demonstrated that an initial cytochrome c release occurred independently of caspase activation and that only caspase-9 activation is partially caspase-independent. The attenuation of GW7845-induced apoptosis by multiple FMK-labeled peptide sequences suggests that multiple caspase pathways are responsible for initiating and executing apoptosis. The strong activation of Bid provides a mechanism by which caspase-2, -3, and -8 may amplify the apoptotic signal. These data support the hypothesis that pharmacologic concentrations of PPAR{gamma} agonists induce an intrinsic apoptotic pathway that is driven in normal bone marrow B cells by multiple amplification loops.

Key Words: PPAR{gamma}; chemotherapy; bone marrow toxicity; apoptosis.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 J. Immunol.Home page
S. L. Bissonnette, J. E. Teague, D. H. Sherr, and J. J. Schlezinger
An Endogenous Prostaglandin Enhances Environmental Phthalate-Induced Apoptosis in Bone Marrow B Cells: Activation of Distinct but Overlapping Pathways
J. Immunol., August 1, 2008; 181(3): 1728 - 1736.
[Abstract] [Full Text] [PDF]


Disclaimer:
Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.