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The regulation of death receptor-med...

Jin, Zhaoyu.

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The regulation of death receptor-mediated apoptosis in tumor cells.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The regulation of death receptor-mediated apoptosis in tumor cells./
作者:	Jin, Zhaoyu.
面頁冊數:	243 p.
附註:	Source: Dissertation Abstracts International, Volume: 66-02, Section: B, page: 0835.
Contained By:	Dissertation Abstracts International66-02B.
標題:	Health Sciences, Pharmacology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3165710
ISBN:	0542006065

The regulation of death receptor-mediated apoptosis in tumor cells.
Jin, Zhaoyu.

The regulation of death receptor-mediated apoptosis in tumor cells. - 243 p.

Source: Dissertation Abstracts International, Volume: 66-02, Section: B, page: 0835.

Thesis (Ph.D.)--University of Pennsylvania, 2005.

Among the identified members of the TNF superfamily of ligands, TNF, FasL and TRAIL are known as death ligands because they are capable of causing cell death. These ligands bind to their receptors to evoke the formation of a death inducing signaling complex (DISC) that is comprised of death receptors, adaptor molecules and initiator caspases. The assembly of a DISC results in the activation of caspase 8 which can activate downstream executioner caspases leading to apoptosis. To better understand how TRAIL sensitivity is regulated in tumor cells, we studied the relationship between cell cycle progression and TRAIL-induced apoptosis. Our results show that G0/G1 arrested cells are more sensitive to TRAIL-induced apoptosis. We also demonstrate that simvastatin and lovastatin (HMG-CoA reductase inhibitors), which can enrich a cancer cell population in G0/G1, can sensitize cells to TRAIL-induced apoptosis in tumor cells, but not in normal keratinocytes. Because the emergence of resistance to apoptosis is a major concern in successful treatment of cancer, and TRAIL survivors may contribute to therapeutic failure, we investigated potential resistance mechanisms. We selected TRAIL-resistant SW480 human colon adenocarcinoma cells. Surprisingly, we found that DISC formation was deficient in multiple selected TRAIL-resistant clones due to dramatic downregulation of DR4 on the cell surface. TRAIL-resistant cells were resensitized to TRAIL by tunicamycin pretreatment, which increased cell surface expression of DR4 and KILLER/DR5. Unlike apoptosis via Fas or TRAIL, how TNF kills cells has been controversial. Here, we provide some novel insights in death-receptor mediated apoptosis by utilizing the RNAi technology. Our data suggests that TRADD and RIP competitively bind to the TNF receptor complex. In addition, we provide evidence that contrary to the widely accepted view, FADD is dispensable in TNF-induced apoptosis, but is responsible for the activation of caspase 8 in complex II following Fas and TRAIL treatment. Rip is a mediator of TNF-induced apoptosis, at least in some cell types. In summary, our studies provide novel insights into the regulation and signaling mechanism of apoptosis induced by death ligands. Understanding the mechanism of death receptor-mediated apoptosis is of significance for their manipulation in therapy.

ISBN: 0542006065Subjects--Topical Terms:

1017717
Health Sciences, Pharmacology.

The regulation of death receptor-mediated apoptosis in tumor cells.
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