The Ubiquitin-Dependent Proteolytic System and other Potenti
Title: The Ubiquitin-Dependent Proteolytic System and other Potential Targets for the Modulation of Nuclear Factor-kB (澳门888真人官网)
VOLUME: 1 ISSUE: 4
Author(s):M. Magnani, R. Crinelli, M. Bianchi and A. Antonelli
Affiliation:Istituto di Chimica BiologicaGiorgio Fornaini Università degli Studi di Urbino, Via A. Saffi, 2 - 61029URBINO, Italy
Keywords:Ubiquitin, Nuclear factor, transcription, matastatic, IKB inhibitor, Anti inflammatory, protesome, mutagenesis
Abstract: Nuclear Factor-kB (澳门888真人官网), is a transcription factor composed of dimeric complexes of p50 (澳门888真人官网1) or p52 (澳门888真人官网2) usually associated with members of the Rel family (p65, c-Rel, Rel B) which have potent transactivation domains. Different combinations of 澳门888真人官网/Rel proteins bind distinct kB sites to regulate the transcription of different genes. In resting cells 澳门888真人官网 resides in the cytoplasm in inactive form, complexed to members of a family of inhibitory proteins referred to as IkB. The bound IkB masks the 澳门888真人官网 nuclear localization signal and thereby inhibits its nuclear transport. 澳门888真人官网 can be activated by a variety of signals relevant to pathophysiology including inflammatory cytokines and bacterial lipopolysaccharides (LPS) as well as oxidative and fluid mechanical stress. Upon activation by these stimuli, IkB is phosphorylated and subsequently degraded. Phosphorylation targets IkB for ubiquitination and degradation by the 26S proteasome thus leading to 澳门888真人官网 nuclear translocation. The same proteolytic pathway is involved in the processing of the p105 and p100 precursors to generate mature p50 and p52 subunits, respectively. Once in the nucleus, 澳门888真人官网 is able to regulate the expression of many genes involved in the immune and inflammatory responses (i.e. inflammatory cytokines and adhesion molecules). Thus, new approaches to modulating 澳门888真人官网 activation, and as a consequence inflammatory or metastatic processes, may take advantage of the selectivity of the ubiquitination and ATP-dependent proteolytic processes leading to IkB turnover. This review will analyze the current strategies aimed at interfering with 澳门888真人官网 activation and will consider the ubiquitination system as a new selective target for the development of new anti-inflammatory therapies.