Abstract
The NF-κB pathway is a critical regulator of immune responses and is often dysregulated in cancer. Two NF-κB pathways have been described to mediate these responses, the canonical and the noncanonical. While understudied compared to the canonical NF-κB pathway, noncanonical NF-κB and its components have been shown to have effects, usually protumorigenic, in many different cancer types. Here, we review noncanonical NF-κB pathways and discuss its important roles in promoting cancer. We also discuss alternative NF-κB-independent functions of some the components of noncanonical NF-κB signaling. Finally, we discuss important crosstalk between canonical and noncanonical signaling, which blurs the two pathways, indicating that understanding the full picture of NF-κB regulation is critical to deciphering how this broad pathway promotes oncogenesis.
Highlights
The Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway is an important regulator of innate and adaptive immune responses, where it regulates responses to pathogens, as well as T and B cell activation [1]
Activation of NF-κB subunits leads to their nuclear translocation and activation of transcription, and the NF-κB pathway is known to regulate the transcription of many genes including proinflammatory cytokines and chemokines (e.g., IL-6 [3]), cell cycle genes, antiapoptotic genes, and extracellular proteases (e.g., matrix metalloprotease 3 (MMP3) [6])
Many combinations of dimers have been observed, the most widely studied dimers are the RelA-p50 dimer, which is primarily activated by canonical NF-κB signaling, and the RelB-p52 dimer, which is activated by noncanonical NF-κB signaling
Summary
The Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway is an important regulator of innate and adaptive immune responses, where it regulates responses to pathogens, as well as T and B cell activation [1]. NF-κB pathway activation leads to transcription regulation by dimers of 5 related transcription factors (RelA/p65, RelB, c-Rel, NFKB1/p105, and NFKB2/p100). The processing of p100 is a critical event in the noncanonical NF-κB pathway, in order to generate the functional p52 transcription factor. This processing removes C-terminal ankyrin repeats, which are similar to those in the IκB proteins that sequester and inhibit the canonical RelA-p50 dimers. P100 binds and inhibits RelB in the absence of an activating signal, and p100 processing is a critical event in the activation of the noncanonical NF-κB pathway [31,32,33]. NIK is stabilized, leading to IKKα containing TRAF2, TRAF3, cIAP1, and cIAP2.
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