© iStockphoto.com/Khuong Hoang
Nuclear factor kappa B (NF-κB) is a family of transcription factors with important roles in eliciting cellular responses to external stimuli. NF-κB normally resides in the cytoplasm of the cell, where it remains in an inactive state bound to an inhibitor of κB (IκB). In response to stimuli, the cell activates IκB kinase (IKK) to degrade IκB, causing NF-κB to become active and move into the nucleus where it regulates gene expression and modifies cell function.
Many different stimuli can trigger IKK and NF-κB activation. The cytokine tumor necrosis factor (TNF), for example, binds TNF receptor type 1 (TNFR1) to trigger the release of TNF receptor-associated factor 2 (TRAF2), which facilitates the attachment of ubiquitin molecules to receptor interacting protein 1 (RIP1). The ubiquitin molecules form a chain that helps RIP1 recruit TGFβ-activated kinase 1 (TAK1) and IKK, providing an opportunity for TAK1 to activate IKK. This cascade of events, known as the TNF signaling pathway, is an important mechanism that keeps immune cells proliferating and stops them from dying.
Apart from cytokines, DNA-damaging agents such as infrared radiation and chemicals can also trigger IKK and NF-κB activation. Previous studies have identified several kinases involved in the DNA-damage signaling pathway, including TAK1 and ataxia telangiestasia mutated (ATM), but the cascade of events leading to IKK and NF-κB activation has been unclear.
Vinay Tergaonkar at the A*STAR Institute of Molecular and Cell Biology and co-workers have now identified a protein called ELKS that acts as a molecular link between ATM and TAK1. They showed that ATM induces the ‘ubiquitination’ of ELKS, which promotes the formation of a TAK1–IKK signaling complex—a sequence analogous to that for TNF signaling.
“When we added DNA-damaging drugs to mouse embryonic fibroblasts derived from ELKS-deficient mice, we did not detect TAK1, IKK or NF-κB activation. However, the mouse embryonic fibroblasts had no problem activating TAK1, IKK or NF-κB in response to TNF. Our findings demonstrate that ELKS plays an important role in the DNA-damage signaling pathway,” says Tergaonkar.
There are some important implications for this finding in cancer treatment. In chemotherapy, cancer cells are known to develop resistance to drugs because of NF-κB activation. Combining chemotherapeutic drugs with NF-κB blockers can overcome chemotherapeutic drug resistance, but this may also inhibit other vital NF-κB functions, such as regulation of immune responses. Combining chemotherapeutic drugs with an ELKS blocker that blocks cellular responses to DNA damage but not to other stimuli would solve all these problems.
The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology.
