tailieunhanh - Báo cáo khoa học: TNFR1-induced activation of the classical NF-jB pathway Harald Wajant1 and Peter Scheurich2

The molecular mechanisms underlying activation of the IjB kinase (IKK) complex are presumably best understood in the context of tumor necrosis factor (TNF) receptor-1 (TNFR1) signaling. In fact, it seems that most, if not all, proteins relevant for this process have been identified and extensive biochemical and genetic data are available for the role of these factors in TNF-induced IKK activation. | ịFEBS Journal MINIREVIEW TNFRI-induced activation of the classical NF-kB pathway Harald Wajant1 and Peter Scheurich2 1 Division of Molecular InternalMedicine Department of InternalMedicine II University HospitalWurzburg Germany 2 Institute of CellBiology and Immunology University of Stuttgart Germany Keywords apoptosis caspase 8 IKK necrosis NF-kB NEMO RIP1 TNF TRADD TRAF2 Correspondence H. Wajant Division of Molecular Internal Medicine MedicalClinic and Polyclinic II University HospitalWurzburg Rontgenring 11 97070 Wurzburg Germany Fax 49 931 201 71O7O Tel 49 931 201 71000 E-mail Received 12 October 2010 revised 9 December 2010 accepted 11 December 2010 The molecular mechanisms underlying activation of the IkB kinase IKK complex are presumably best understood in the context of tumor necrosis factor TNF receptor-1 TNFR1 signaling. In fact it seems that most if not all proteins relevant for this process have been identified and extensive biochemical and genetic data are available for the role of these factors in TNF-induced IKK activation. There is evidence that protein modificationindependent assembly of a core TNFR1 signaling complex containing TNFR1-associated death domain receptor interacting kinase 1 TNF receptor-associated factor 2 and cellular inhibitor of apoptosis protein 1 and 2 starts a chain of nondegrading ubiquitination events that culminate in the recruitment and activation of IKK complex-stimulating kinases and the IKK complex itself. Here we sum up the known details of TNFR1-induced IKK activation address arising contradictions and discuss possible explanations resolving the apparent discrepancies. doi The NF-kB system The nuclear factor of kappa B NF-kB proteins are dimeric transcription factors composed of five different subunits namely p65 RelA RelB cRel p50 and p52. In unstimulated cells the NF-kB transcription dimers are retained in the cytoplasm in an inactive state by .