如题所述
第1个回答 2024-06-17
Nuclear Factor-kB (NF-kB), a crucial transcription factor, plays a pivotal role in controlling numerous genes fundamental to processes such as apoptosis, viral replication, tumorigenesis, inflammation, and autoimmune disorders. This signaling pathway is believed to be part of the body's stress response mechanism, as it becomes activated by various stimuli, including growth factors, cytokines, lymphokines, ultraviolet radiation, pharmacological agents, and stress. In its resting state, NF-kB is sequestered in the cytoplasm, bound by inhibitor proteins from the IkB family, including IkBa, IkBb, IkBg, and IkBe.
Upon activation, NF-kB activation is triggered by stimuli-induced phosphorylation of IkB proteins. Following this event, IkB undergoes ubiquitination and is subsequently degraded, releasing the nuclear localization signals (NLS) on NF-kB subunits. This allows the protein to translocate from the cytoplasm to the nucleus. Inside the nucleus, NF-kB binds to specific consensus DNA sequences (5'GGGACTTTCC-3') found in various genes, thereby modulating their transcription. The activation process is facilitated by the IkB kinase complex, which consists of at least three proteins: IKK1/IKKa, IKK2/IKKb, and IKK3/IKKg. These enzymes phosphorylate IkB, ultimately leading to its degradation.
Tumor necrosis factor (TNF), a well-studied activator, initiates the process by binding to its receptor and recruiting TNF receptor death domain (TRADD). TRADD, in turn, binds to TNF receptor-associated factor 2 (TRAF-2), which then attracts NF-kB-inducible kinase (NIK). Both IKK1 and IKK2 possess sequences that can be phosphorylated by the MAP kinase NIK/MEKK1, independently activating IkBa or IkBb. Another component, A20, a zinc finger protein, is induced by NF-kB activators. A20 acts as a negative regulator, preventing TRAF2 from further activating NF-kB, and it also inhibits TNF and IL-1-induced NF-kB activation, indicating its potential as a general inhibitor of NF-kB signaling.
Upon activation, NF-kB activation is triggered by stimuli-induced phosphorylation of IkB proteins. Following this event, IkB undergoes ubiquitination and is subsequently degraded, releasing the nuclear localization signals (NLS) on NF-kB subunits. This allows the protein to translocate from the cytoplasm to the nucleus. Inside the nucleus, NF-kB binds to specific consensus DNA sequences (5'GGGACTTTCC-3') found in various genes, thereby modulating their transcription. The activation process is facilitated by the IkB kinase complex, which consists of at least three proteins: IKK1/IKKa, IKK2/IKKb, and IKK3/IKKg. These enzymes phosphorylate IkB, ultimately leading to its degradation.
Tumor necrosis factor (TNF), a well-studied activator, initiates the process by binding to its receptor and recruiting TNF receptor death domain (TRADD). TRADD, in turn, binds to TNF receptor-associated factor 2 (TRAF-2), which then attracts NF-kB-inducible kinase (NIK). Both IKK1 and IKK2 possess sequences that can be phosphorylated by the MAP kinase NIK/MEKK1, independently activating IkBa or IkBb. Another component, A20, a zinc finger protein, is induced by NF-kB activators. A20 acts as a negative regulator, preventing TRAF2 from further activating NF-kB, and it also inhibits TNF and IL-1-induced NF-kB activation, indicating its potential as a general inhibitor of NF-kB signaling.
