Characterization of apoptosis and survival signaling through activation of the ER-stress response by Shiga toxin type 1 in undifferentiated and differentiated THP-1 cells : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
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[College Station, Tex.] :
[Texas A&M University System Health Science Center],
[2010]
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| Subjects: |
| Abstract: | ABSTRACT: The purpose of this study is to understand how Shiga toxin type 1-induced ER stress affects various signaling pathways underlying programmed cell death and survival in THP-1 myeloid cells undergoing maturation from the monocytic to the macrophage-like state. Although significantly improved hygenic conditions have reduced the incidence of infectious diseases caused by the human pathogens, Shiga toxin-producing Shigella dysenteriae serotype 1 and Shiga toxin-producing Escherichia coli (STEC), these bacteria remain a major health concern due to the severity of extra-intestinal diseases they cause, including central nervous system complications and acute renal failure (as a result of the hemolytic uremic syndrome). Shiga toxins are the key virulence factors expressed by these pathogens. The toxins penetrate and cross the intestinal epithelium, circulate in the bloodstream, attach to susceptible cells via a unique glycolipid receptor, are internalized and undergo retrograde intracellular trafficking. Delivery of the toxins to the endoplasmic reticulum (ER) results in host cell protein synthesis inhibition, activation of the ER stress response, and in some cases, the induction of apoptosis. Pro-apoptotic factors are involved in executing cell death by stimulating intrinsic and/or extrinsic apoptosis inducing pathways. Shiga toxin type 1 activates components of both intrinsic and extrinsic pathways in THP-1 cells. The toxin also simultaneously activates cell survival signaling pathways in differentiated THP-1 cells, including the anti-apoptotic factors Bcl-2 and IAP family members. Shiga toxin type 1-induced Ca²⁺⁺ release from intracellular stores affects calpain activation and subsequent activation of apoptotic effectors such as caspases. In this project, we demonstrated that, via the intrinsic pathway of apoptosis induction, increased expression of the anti-apoptotic factor Bcl-2 was associated with protection from rapid apoptosis induced by the Shiga toxin type 1 in macrophage-like THP-1 cells under ER stress, while Bcl-2 expression was decreased in monocytic THP-1 cells leading to rapid apoptosis in the presence of Shiga toxin type 1. Finally, Shiga toxin type 1 activated the extrinsic pathway of apoptosis via ER stress leading to CHOP-DR5 signaling and calpain activation, both of which differentially contributed to myeloid cell maturation-dependent toxin-induced apoptosis. Silencing of these signaling pathways may protect cells from Shiga toxin-mediated cytotoxicity. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Office of Research and Graduate Studies of The Texas A&M University System Health Science Center in partial fulfillment of the requirements for the degree of Doctor of Philosophy May 2010." Approved as to style and content by: Vernon L. Tesh, C. Nick Pace, John M. Quarles, James E. Samuel, Jonathan T. Skare. |
| Physical Description: | x, 138 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 112-136). |