Regulation of NF (kappa) B-Dependent Cell Survival Signals Through the SCF (Slimb) Ubiquitin Ligase Pathway
Abstract
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 the 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 cytokines such as TNFalpha. These kinases phosphorylate IkB, thereby activating it for ubiquitinaton. Ubiguitination involves 3 activities: an El activating enzyme, an E2 ubiguitin conjugating enzyme, and an E3 ubiguitin-protein ligase. In work supported by this grant, we have identified the molecular components involved in IkB ubiguitination. The ubiguitin ligase is composed of Skpl/Cull/Rbxl and the specificity factor beta-TRCP. We have also performed a series of biochemical experiments that have revealed a consensus sequence for association of TRCP with ubiguitination substrates and have identified residues in TRCP that function in substrate recognition.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2002
- Accession Number
- ADA407554
Entities
People
- Jeffrey Harper
Organizations
- Baylor College of Medicine