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Sci. Signal., 30 March 2010
Vol. 3, Issue 115, p. re4
[DOI: 10.1126/scisignal.3115re4]

REVIEWS

The Role of the Kinases RIP1 and RIP3 in TNF-Induced Necrosis

Peter Vandenabeele1,2*, Wim Declercq1,2, Franky Van Herreweghe1,2, and Tom Vanden Berghe1,2

1 Molecular Signaling and Cell Death Unit, Department for Molecular Biomedical Research, VIB, 9052 Zwijnaarde, Belgium.
2 Department of Biomedical Molecular Biology, Ghent University, 9052 Zwijnaarde, Belgium.

Gloss: The history of tumor necrosis factor (TNF) incorporates many facets of cell biology, immunology, and pathophysiology. The historical name "TNF" emphasizes its capacity to induce hemorrhagic necrosis of tumors, which refers to a histological feature. However, TNF is now known as a multifunctional cytokine that mediates cell death and inflammation following infection or tissue injury. The ability of TNF to cause cachexia and wasting during chronic neoplastic and infectious diseases suggests a link with metabolism. Here, we report on the different signaling pathways that determine whether the cellular outcome of TNF signaling is gene induction and survival, apoptosis, or programmed necrosis. Programmed necrosis is also called necroptosis, a regulated form of necrotic cell death that occurs in the absence of caspase activation and that can be blocked by inhibiting RIP1 (receptor-interacting protein 1). The kinases RIP1 and RIP3, which are regulated by caspases and ubiquitination, are key initiators of programmed necrosis. However, it remains unclear precisely how RIP1 and RIP3 instigate the execution pathways of programmed necrosis, which involve several cellular processes, such as increased bioenergetics, increased reactive oxygen species production, calcium mobilization, activation of phospholipases and acid sphingomyelinases, and destabilization of lysosomes. Because necrosis occurs in different conditions—such as myocardial infarction, stroke, pancreatitis, and viral infections—kinase inhibitors of RIP1 and RIP3 could be used or developed to prevent pathological cell death. This review highlights TNF-induced mechanisms of programmed necrosis mediated by the kinases RIP1 and RIP3, and contains three figures and 102 references.

* Corresponding author. E-mail, Peter.Vandenabeele{at}dmbr.UGent.be

Citation: P. Vandenabeele, W. Declercq, F. Van Herreweghe, T. Vanden Berghe, The Role of the Kinases RIP1 and RIP3 in TNF-Induced Necrosis. Sci. Signal. 3, re4 (2010).


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