Regulation of NF-κB by atypical activators and tumour suppressors

The RelA(p65) NF-κB (nuclear factor κB) subunit is typically thought of as being antiapoptotic and tumourpromoting. However, in our laboratory, we have discovered that RelA can inhibit, rather than induce, antiapoptotic gene expression when activated by certain chemotherapeutic drugs, UV light or through the action of the ARF tumour suppressor. These observations explain why RelA can sometimes facilitate rather than inhibit apoptosis and also exhibits tumour-suppressor characteristics in vivo. A better understanding of these processes and an ability to analyse RelA function in tumours could lead to improved cancer diagnosis, choice of therapy and, ultimately, development of new drugs. NF-κB (nuclear factor κB) transcription factor complexes consist of homodimers and heterodimers formed from the multigene NF-κB-Rel family: RelA(p65), RelB, c-Rel, p105p50 (NF-κB1) and p100-p52 (NF-κB2 or lyt-10). All contain an approx. 300-amino-acid region in their N-termini, termed the RHD (Rel homology domain), which mediates DNA binding and dimerization [1,2]. RelA(p65), RelB and c-Rel contain non-homologous transactivation domains in their C-termini. p105 and p100 require proteolytic processing to generate their active non-DNA-binding forms, p50 and p52. One of the most studied NF-κB subunits is the RelA (or p65) subunit, which is expressed ubiquitously and is often found as a heterodimer with the p50 subunit [1]. In most non-stimulated, untransformed cells, RelA-containing NF-κB complexes are held in an inactive cytoplasmic form, bound to one of a family of inhibitor proteins, the IκBs (inhibitory κBs) [1]. Induction of DNA binding generally results from activation of the IκB–kinase (IKK) signalosome complex, which phosphorylates one of the IκBs, α, β or ε, promoting their ubiquitination and degradation by the proteasome [3]. This releases the RelA complex, allowing it to translocate to the nucleus. The function of NF-κB and its role in cancer Gene knockouts in mice and other experiments have demonstrated the importance of NF-κB subunits as regulators of immune-cell function and the inflammatory response in addition to their role in inflammatory diseases [4–6]. It has now become apparent, however, that aberrant activation and nuclear localization of NF-κB in cancer is common. This most often arises from defects in upstream signalling pathways regulating IKK and NF-κB activities or from the microenvironment of a solid tumour, which frequently contains