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Molecular and Cellular Biology, November 2003, p. 7829-7837, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7829-7837.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Diarylurea Compounds Inhibit Caspase Activation by Preventing the Formation of the Active 700-Kilodalton Apoptosome Complex

Ulrik Lademann,1 Kelvin Cain,2 Mads Gyrd-Hansen,1 David Brown,2 Dan Peters,3 and Marja Jäättelä1*

Apoptosis Laboratory, Institute of Cancer Biology, Danish Cancer Society, DK-2100 Copenhagen,1 NeuroSearch A/S, DK-2750 Ballerup, Copenhagen, Denmark,3 MRC Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom2

Received 18 November 2002/ Returned for modification 17 December 2002/ Accepted 25 June 2003

The release of mitochondrial proapoptotic proteins into the cytosol is the key event in apoptosis signaling, leading to the activation of caspases. Once in the cytosol, cytochrome c triggers the formation of a caspase-activating protein complex called the apoptosome, whereas Smac/Diablo and Omi/htra2 antagonize the caspase inhibitory effect of inhibitor of apoptosis proteins (IAPs). Here, we identify diarylurea compounds as effective inhibitors of the cytochrome c-induced formation of the active, approximately 700-kDa apoptosome complex and caspase activation. Using diarylureas to inhibit the formation of the apoptosome complex, we demonstrated that cytochrome c, rather than IAP antagonists, is the major mitochondrial caspase activation factor in tumor cells treated with tumor necrosis factor. Thus, we have identified a novel class of compounds that inhibits apoptosis by blocking the activation of the initiator caspase 9 by directly inhibiting the formation of the apoptosome complex. This mechanism of action is different from that employed by the widely used tetrapeptide inhibitors of caspases or known endogenous apoptosis inhibitors, such as Bcl-2 and IAPs. Thus, these compounds provide a novel specific tool to investigate the role of the apoptosome in mitochondrion-dependent death paradigms.

* Corresponding author. Mailing address: Apoptosis Laboratory, Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. Phone: 45-35257318. Fax: 45-35257721. E-mail: mhj{at}biobase.dk.

Molecular and Cellular Biology, November 2003, p. 7829-7837, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7829-7837.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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