Description
Activation of the NF-κB pathway can be triggered by many factors including TNFα, UV, IL-1, lipopolysaccharide (LPS), mitogens, and phorbol esters. NF-κB,also called RELA, is controlled by a family of inhibitory proteins called, IκBs. IκB proteins are phosphorylated by IκB kinase complex consisting of at least three proteins, IKK1/α, IKK2/β, and IKK3/γ. External stimuli such as tumor necrosis factor or other cytokines initiate a signal transduction cascade that leads to the activation of IκB-kinase complex, which then specifically phosphorylates IκBα on Serine-32 and Serine-36. Phosphorylation of these sites leads to ubiquitination of IκBα and subsequent degradation by the 26 S proteasome. Degradation of IκBα results in unmasking of the nuclear localization signal of NF-κB dimers, which subsequently translocates to the nucleus and acts as a transcription factor for genes controlling inflammatory cytokines, adhesion molecules, and other proteins. Thus the nuclear levels of p65 may correlate positively with the activation of NF-κB pathway