Tumor suppressor ARF: The new player of innate immunity

Abstract

ARF (alternative reading frame) is one of the most important tumor regulator playing critical roles in controlling tumor initiation and progression. Recently, we have demonstrated a novel and unexpected role for ARF as modulator of inflammatory responses.

Figure 1. Model of the regulation of inflammatory response by ARF. In normal cells, inflammatory stimuli induce NF-κB signaling pathways through the phosphorylation and subsequent ubiquitin-dependent degradation of IκBα by the 26S proteasome. Then, NF-κB translocates to the nucleus inducing target gene expression. ARF present in the nucleus, displays physical and functional interaction with E2F1 resulting in destabilization of E2F1 protein and activation of NF-κB. However, in the ARF-deficient macrophages, (p65/p50)NF-κB translocates to the nucleus but excessive E2F1 inhibits NF-κB by binding to its subunit p65 in competition with the heterodimeric partner p50. Moreover, excessive E2F1 may inhibit transcriptional expression of TLRs.