Nuclear Factor Kappa B: Signaling Mechanisms, Cellular Responses, and Cell-Cycle Regulation

Abstract

Nuclear factor kappa B (NF-κB) is a family of inducible transcription factors that integrates inflammatory, immune, survival, stress, and proliferative signals. Its activity is controlled by receptor-proximal signaling, the IκB kinase system, inhibitory IκB proteins, ubiquitin-dependent protein processing, and nuclear interactions with κB DNA elements. This review summarizes the molecular organization of NF-κB and follows its activation from cell-surface receptors to transcriptional regulation. Particular emphasis is placed on the distinction between the canonical pathway, which commonly uses IKKβ/NEMO-dependent IκB degradation and p50/RelA nuclear translocation, and the non-canonical pathway, which depends on NF-κB-inducing kinase, IKKα, and p100 processing to generate p52/RelB. Downstream NF-κB activity regulates cytokines, chemokines, adhesion molecules, inflammatory enzymes, anti-apoptotic proteins, immune-cell differentiation, organelle function, and metabolic adaptation. NF-κB also influences cell-cycle progression through cyclin D proteins, CDK4/6, c-Myc, and interconnected survival pathways. Because physiological and pathological NF-κB functions are strongly context dependent, future therapeutic research should prioritize spatially, temporally, and cell-type-selective pathway modulation rather than indiscriminate systemic inhibition.