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Molecular and Cellular Biology, February 2003, p. 1278-1291, Vol. 23, No. 4
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.4.1278-1291.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Erythroid Differentiation Sensitizes K562 Leukemia Cells to TRAIL-Induced Apoptosis by Downregulation of c-FLIP

Ville Hietakangas,1,2 Minna Poukkula,1,3 Kaisa M. Heiskanen,1,3,4 Jarkko T. Karvinen,5 Lea Sistonen,1,4 and John E. Eriksson1,3*

Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FIN-20521 Turku,1 Department of Biochemistry and Food Chemistry,2 Department of Biology, University of Turku, FIN-20014 Turku,3 Department of Biology, Åbo Akademi University, FIN-20520 Turku,4 Wallac Oy, PerkinElmer Life Sciences, FIN-20101 Turku, Finland5

Received 16 July 2002/ Returned for modification 21 August 2002/ Accepted 18 November 2002

Regulation of the apoptotic threshold is of great importance in the homeostasis of both differentiating and fully developed organ systems. Triggering differentiation has been employed as a strategy to inhibit cell proliferation and accelerate apoptosis in malignant cells, in which the apoptotic threshold is often characteristically elevated. To better understand the mechanisms underlying differentiation-mediated regulation of apoptosis, we have studied death receptor responses during erythroid differentiation of K562 erythroleukemia cells, which normally are highly resistant to tumor necrosis factor (TNF) alpha-, FasL-, and TRAIL-induced apoptosis. However, upon hemin-mediated erythroid differentiation, K562 cells specifically lost their resistance to TNF-related apoptosis-inducing ligand (TRAIL), which efficiently killed the differentiating cells independently of mitochondrial apoptotic signaling. Concomitantly with the increased sensitivity, the expression of both c-FLIP splicing variants, c-FLIPL and c-FLIPS, was downregulated, resulting in an altered caspase 8 recruitment and cleavage in the death-inducing signaling complex (DISC). Stable overexpression of both c-FLIPL and c-FLIPS rescued the cells from TRAIL-mediated apoptosis with isoform-specific effects on DISC-recruited caspase 8. Our results show that c-FLIPL and c-FLIPS potently control TRAIL responses, both by distinct regulatory features, and further imply that the differentiation state of malignant cells determines their sensitivity to death receptor signals.

* Corresponding author. Mailing address: Turku Centre for Biotechnology, P.O. Box 123, FIN-20521 Turku, Finland. Phone: 358-2-333-8036. Fax: 358-2-333-8000. E-mail: john.eriksson{at}utu.fi.

Molecular and Cellular Biology, February 2003, p. 1278-1291, Vol. 23, No. 4
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.4.1278-1291.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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