Regulation of NF (kappa) B-Dependent Cell Survival Signals Through the SCF (Slimb) Ubiquitin Ligase Pathway.

摘要

NFkB is a transcription factor that functions to block the apoptotic response. Inappropriate activation of NFkB is thought to block apoptosis in breast cancer cells. NfkB activity is negatively regulated by a signaling pathway that responds to extracellular signals, including cytokines. Normally, NFkB is held in cytoplasm by its inhibitor, IkB. In response to extracellular signals, IkB is destroyed by the process of ubiquitin mediated proteolysis. This process is activated through protein kinases that respond to cytokine% such as TNFalpha. These kinases phosphorylate IkB, thereby activating it for ubiquitination. Ubiquitination% involves 3 activities: an El activating enzyme, an E2 ubiquitin conjugating enzyme, and an E3 ubiquitin- protein ligase. In work supported by this grant, we have identified the molecular components involved in ubiquitination. The ubiquitin ligase is composed of Skp1/Cull/Rbx1 and the specificity factor beta-TRCP. Beta-TRCP binds IkB in a phosphorylation dependent manner and targets it for ubiquitination via the SCF pathway. These data suggest that molecules which interfere with IkB ubiquitination by the SCF beta-TRCP complex could function as anti-apoptotic agents.