The Direct and Indirect Roles of NF-κB in Cancer: Lessons from Oncogenic Fusion Proteins and Knock-in Mice

Abstract

NF-κB signaling pathways play an important role in the regulation of cellular immune and stress responses. Aberrant NF-κB activity has been implicated in almost all the steps of cancer development and many of the direct and indirect contributions of this transcription factor system for oncogenesis were revealed in the recent years. The indirect contributions affect almost all hallmarks and enabling characteristics of cancer, but NF-κB can either promote or antagonize these tumor-supportive functions, thus prohibiting global NF-κB inhibition. The direct effects are due to mutations of members of the NF-κB system itself. These mutations typically occur in upstream components that lead to the activation of NF-κB together with further oncogenesis-promoting signaling pathways. In contrast, mutations of the downstream components, such as the DNA-binding subunits, contribute to oncogenic transformation by affecting NF-κB-driven transcriptional output programs. Here, we discuss the features of recently identified oncogenic RelA fusion proteins and the characterization of pathways that are regulating the transcriptional activity of NF-κB by regulatory phosphorylations. As NF-κB's central role in human physiology prohibits its global inhibition, these auxiliary or cell type-specific NF-κB regulating pathways are potential therapeutic targets.

Keywords: NF-κB; cancer; transcription.

Figure 1

DNA-binding subunits of NF-κB. The functional domains of the five DNA-binding subunits, including the leucine zipper (LZ), the glycine-rich region (GRR), and the death domain (DD) are shown. The number of amino acids is given for the human proteins.

Figure 2

Schematic summary of the phenotypes of the p65 (RelA) knock-in mice mutated at the indicated phosphorylation sites.

Figure 3

Schematic summary of the indirect roles of NF-κB for the hallmarks and enabling characteristics of cancer. The relative thickness of the arrows indicates the estimated relative contribution of NF-κB for the support (arrow up) or antagonism (arrow down) for the indicated processes.

Figure 4

Schematic display of mutations occurring at upstream or downstream components of the NF-κB system. Mutations of upstream regulators are exemplified by the gain-of-function (GOF) mutations in the CBM complex that typically lead to activation of further tumor-promoting signaling pathways.

Figure 5

Schematic summary of oncogenic NF-κB DNA-binding subunits. The color code is similar to Figure 1, the v-Rel protein contains short sequence remnants from the REV env (envelope) gene at the N- and C-termini. Different parts of the C11ORF95 proteins, which contain zinc fingers (ZnF) are fused to the N-termini of p65.