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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

TRAIL resistance through transcriptional control of MCL-1

Son, Jae Kyoung 04 June 2010 (has links)
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potentially useful anticancer agent with exquisite selectivity for cancer cells. Unfortunately, many cancers exhibit or acquire resistance to TRAIL. We report herein that TRAIL activates a TGF-ß-activated kinase 1→mitogen-activated protein kinase (MAPK) kinase 3 (MKK3)/MKK6→p38 pathway in prostate cancer cells that transcriptionally upregulates expression of the antiapoptotic BCL-2 family member MCL-1. TRAIL alone triggered robust formation of the "death-inducing signaling complex", activation of the initiator caspase-8, and truncation of the BH3-only protein BID (tBID). Nevertheless, simultaneous disruption of the p38 MAPK pathway was required to suppress MCL-1 expression, thereby allowing tBID to activate the proapoptotic BCL-2 family member BAK and stimulate mitochondrial outer membrane permeabilization (MOMP). Release of the inhibitor-of-apoptosis antagonist, Smac/DIABLO, from the intermembrane space was sufficient to promote TRAIL-induced apoptosis, whereas release of cytochrome c and apoptosome function were dispensable. Even following MOMP, however, mitochondrial-generated reactive oxygen species activated a secondary signaling pathway, involving c-Jun N-terminal kinases, that likewise upregulated MCL-1 expression and partially rescued cells from death. Thus, stress kinases activated at distinct steps in the extrinsic pathway mediate TRAIL resistance through maintenance of MCL-1 expression. / text

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