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First published online October 13, 2004
doi: 10.1242/10.1242/jcs.01483

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Linking JNK signaling to NF-B: a key to survival

Salvatore Papa, Francesca Zazzeroni^*, Can G. Pham, Concetta Bubici and Guido Franzoso

The Ben May Institute for Cancer Research, The University of Chicago, 924 East 57th Street, Chicago, IL 60637, USA

View larger version (30K): [in a new window]   Fig. 1. TNFR1-induced pathways modulating apoptosis. Formation of complex I leads to NF-B activation, Gadd45ß induction, JNK inhibition and cell survival. Formation of complex II leads to caspase-8/10-mediated cleavage of Bid into tBid, which then targets mitochondria to induce cytochrome c release and, ultimately, cell death. The figure also depicts JNK activation, which results in formation of jBid; this promotes PCD by triggering release of Smac/Diablo into the cytosol, inhibiting the TRAF2-IAP1 complex and consequently activating caspase-8. The Gadd45ß-MKK7 interaction linking the JNK and NF-B pathways is also shown.

View larger version (11K): [in a new window]   Fig. 2. The various mediators of the NF-B suppression of JNK signaling and their potential modes of action.

View larger version (17K): [in a new window]   Fig. 3. Potential therapeutic implications of the NF-B-mediated blockade of TNF--induced JNK signaling. A positive-feedback loop between TNF- and NF-B drives chronic inflammatory states; several pharmacological agents can be used to treat these states. The effects of MKK7-mimicking peptides are also shown (Papa et al., 2004), which support the therapeutic feasibility of blocking the NF-B anti-apoptotic activity without significantly affecting the immune system.