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A novel mechanism of CD40-induced apoptosis of carcinoma cells involving TRAF3 and JNK/AP-1 activation

Georgopoulos, N T, Steele, L P, Thomson, M J, Selby, P J, Southgate, J and Trejdosiewicz, L K 2006, A novel mechanism of CD40-induced apoptosis of carcinoma cells involving TRAF3 and JNK/AP-1 activation, Cell Death and Differentiation, vol. 13, no. 10, pp. 1789-1801, doi: 10.1038/sj.cdd.4401859.

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Title A novel mechanism of CD40-induced apoptosis of carcinoma cells involving TRAF3 and JNK/AP-1 activation
Author(s) Georgopoulos, N T
Steele, L P
Thomson, M J
Selby, P J
Southgate, J
Trejdosiewicz, L K
Journal name Cell Death and Differentiation
Volume number 13
Issue number 10
Start page 1789
End page 1801
Total pages 13
Publisher Nature Publishing Group
Place of publication London, UK
Publication date 2006
ISSN 1350-9047
Keyword(s) Apoptosis
Carcinoma
CD40
Human
Urothelium
Summary Membrane-presented CD40 agonists can induce apoptosis in carcinoma, but not normal homologous epithelial cells, whereas soluble agonists are growth inhibitory but not proapoptotic unless protein synthesis is blocked. Here we demonstrate that membrane-presented CD40 ligand (CD154) (mCD40L), but not soluble agonists, triggers cell death in malignant human urothelial cells via a direct mechanism involving rapid upregulation of TNFR-associated factor (TRAF)3 protein, without concomitant upregulation of TRAF3 mRNA, followed by activation of the c-Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) pathway and induction of the caspase-9/caspase-3-associated intrinsic apoptotic machinery. TRAF3 knockdown abrogated JNK/AP-1 activation and prevented CD40-mediated apoptosis, whereas restoration of CD40 expression in CD40-negative carcinoma cells restored apoptotic susceptibility via the TRAF3/AP-1-dependent mechanism. In normal human urothelial cells, mCD40L did not trigger apoptosis, but induced rapid downregulation of TRAF2 and 3, thereby paralleling the situation in B-lymphocytes. Thus, TRAF3 stabilization, JNK activation and caspase-9 induction define a novel pathway of CD40-mediated apoptosis in carcinoma cells.
Language eng
DOI 10.1038/sj.cdd.4401859
Field of Research 111201 Cancer Cell Biology
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Persistent URL http://hdl.handle.net/10536/DRO/DU:30061412

Document type: Journal Article
Collections: Faculty of Health
School of Medicine
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