Figure 2.

Crosstalk between ionizing radiation-induced apoptosis and NF-κB pathway. IR activates both apoptosis and NF-κB signaling pathway. IR triggers instrinsic apoptosis pathway as described in Figure 1. Simultaneously, NF-κB pathway is activated by IR-induced DNA damage. IR induced double-strand breaks (DSB) directly activates initiator kinase ATM and PIDD, which further recruit NEMO, also known as IKKγ, by multiple steps of posttranslational modification. Modified NEMO joins formation of IKKs signalosome and further activates classical NF-κB pathway. Upon apoptotic stimuli (IR or TNFα), natural Smac can bind to both XIAP and cIAPs, and predominantly neutralize the suppression effect of XIAP on caspases. It has been shown that cIAP-1 physically binds to TRAF2 and regulates its function through ubiquitination in TNFα signaling. Smac-mimetics that function as IAP-antagonists, not only promote caspase activation by neutralizing IAPs, but also interferes the stability and interaction between cIAP-1/2 and TRAF2, thus modulate the balance between apoptosis and NF-κB signaling pathway.