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

N. T. Georgopoulos, L. P. Steele, M. J. Thomson, P. J. Selby, J. Southgate, L. K. Trejdosiewicz

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1789-1801
Number of pages13
JournalCell Death and Differentiation
Volume13
Issue number10
Early online date20 Jan 2006
DOIs
Publication statusPublished - 1 Oct 2006
Externally publishedYes

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TNF Receptor-Associated Factor 3
JNK Mitogen-Activated Protein Kinases
Transcription Factor AP-1
Apoptosis
Carcinoma
Caspase 9
Up-Regulation
TNF Receptor-Associated Factor 2
CD40 Ligand
Membranes
Caspase 3
Proteins
B-Lymphocytes
Cell Death
Down-Regulation
Epithelial Cells
Messenger RNA
Growth

Cite this

Georgopoulos, N. T. ; Steele, L. P. ; Thomson, M. J. ; Selby, P. J. ; Southgate, J. ; Trejdosiewicz, L. K. / A novel mechanism of CD40-induced apoptosis of carcinoma cells involving TRAF3 and JNK/AP-1 activation. In: Cell Death and Differentiation. 2006 ; Vol. 13, No. 10. pp. 1789-1801.
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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.; Trejdosiewicz, L. K.

In: Cell Death and Differentiation, Vol. 13, No. 10, 01.10.2006, p. 1789-1801.

Research output: Contribution to journalArticle

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