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Molecular and Cellular Biology, September 1999, p. 5991-6002, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Inhibition of Mitogen-Activated Kinase Signaling Sensitizes HeLa Cells to Fas Receptor-Mediated Apoptosis

Tim H. Holmström,1,2,3 Stefanie E. F. Tran,1,2,3 Victoria L. Johnson,4 Natalie G. Ahn,5 Sek C. Chow,4 and John E. Eriksson1,*

Turku Centre for Biotechnology1 and Turku Graduate School of Biomedical Sciences,2 University of Turku and Åbo Akademi University, FIN-20521 Turku,1 and Department of Biology, Åbo Akademi University, BioCity, FIN-20520 Turku,3 Finland; Centre for Mechanism of Human Toxicity, University of Leicester, Leicester LE1 9HN, United Kingdom4; and Howard Hughes Medical Institute, Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 803095

Received 30 November 1998/Returned for modification 28 January 1999/Accepted 26 May 1999

The Fas receptor (FasR) is an important physiological mediator of apoptosis in various tissues and cells. However, there are also many FasR-expressing cell types that are normally resistant to apoptotic signaling through this receptor. The mitogen-activated protein kinase (MAPK) signaling cascade has, apart from being a growth-stimulating factor, lately received attention as an inhibitory factor in apoptosis. In this study, we examined whether MAPK signaling could be involved in protecting FasR-insensitive cells. To this end, we used different approaches to inhibit MAPK signaling in HeLa cells, including treatment with the MAPK kinase inhibitor PD 98059, serum withdrawal, and expression of dominant-interfering MAPK kinase mutant protein. All of these treatments were effective in sensitizing the cells to FasR-induced apoptosis, demonstrating that MAPK indeed is involved in the control of FasR responses. The MAPK-mediated control seemed to occur at or upstream of caspase 8, the initiator caspase in apoptotic FasR responses. Transfection with the constitutively active MAPK kinase abrogated FasR-induced apoptosis also in the presence of cycloheximide, indicating that the MAPK-generated suppression of FasR-mediated apoptotic signaling is protein synthesis independent. In cells insensitive to FasR-induced apoptosis, stimulation of the FasR with an agonistic antibody resulted in significant MAPK activation, which was inhibited by PD 98059. When different cell types were compared, the FasR-mediated MAPK activation seemed proportional to the degree of FasR insensitivity. These results suggest that the FasR insensitivity is likely to be a consequence of FasR-induced MAPK activation, which in turn interferes with caspase activation.

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

Molecular and Cellular Biology, September 1999, p. 5991-6002, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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