Aaron Ciechanover, MD, DSc
Distinguished Technion Professor
MD, 1974 - Hebrew University, Israel
DSc, 1982 - Technion, Israel
Role of ubiquitin system in the generation of NF-κB from its inactive precursor: implications for cancer pathogenesis and development of novel therapeutic modalities
Modification of proteins by ubiquitin and ubiquitin-like proteins affects their stability, function or cellular localization, and is involved in regulation of most cellular processes, including transcription, differentiation, cell cycle and division, and maintenance of quality control. The finding that modification by the same protein can control a broad array of functions is due not only to its numerous cellular targets, but also to the evolvement of multiple signals where different polymers of ubiquitin and ubiquitin-like proteins serve different functions. We are studying the different signals that target proteins to proteasomal degradation, limited processing, and autophagy, in order to understand how the fate of a target substrate is determined by the unique nature of its modification. One specific subject is the generation of active NF-κB from an inactive longer precursor – a process that requires a unique modification by several single moieties of ubiquitin. The generation of this factor, which supports promotion of tumors by suppressing cell death and promoting cell division, is therefore an ideal target for novel anti-cancer therapies we are involved in developing.
1. Upper panel: A 3D structure of the ubiquitin molecule. Marked are alpha helices (violet), beta sheets (green), backbone (green), Met1 and Gly76 (N- and C-terminal residues, respectively) (yellow), Leu8, Ile44, and Val70 that constitute the hydrophobic patch required for ubiquitin interaction with other downstream effectors (yellow), and Lys48 and Lys63 involved in most internal linkages in ubiquitin polymers (Lys48 mostly in proteasomal degradation and Lys63 mostly in signaling).
2.Lower panel: A stamp issued by the Israeli philatelic authority to celebrate the International Year of Chemistry (2011). The stamp shows the 3D structure of ubiquitin, commemorating the 2004 Nobel Prize in Chemistry awarded to the ubiquitin system discoverers – Ciechanover, Hershko, and Rose.
Shabek N, Herman-Bachinsky Y, Buchsbaum S, Lewinson O, Haj-Yahya M, Hejjaoui M, Lashuel HA, Sommer T, Brik A, Ciechanover A. 2012. The Size of the Proteasomal Substrate Determines whether its Degradation will be Mediated by Mono- or Polyubiquitylation. Mol. Cell 48, 87-97.
(Reviewed by F1000 -http://f1000.com/717953569#comments and by Nature Reviews in Cell and Molecular Biology -http://www.nature.com/nrm/journal/v13/n10/full/nrm3445.html?WT.ec_id=NRM-201210)
Weissman AM, Shabek N, Ciechanover A. 2011. The Predator Becomes the Prey: Regulating the Ubiquitin System by Ubiquitylation and Degradation. Nature Rev. Mol. Cell. Biol.12, 605-620.
Kravtsova-Ivantsiv Y, Cohen S, Ciechanover A. 2009. Modification by Single Ubiquitin Moieties Rather Than Polyubiquitination is Sufficient for Proteasomal Processing of the p105 NF-kB Precursor. Mol. Cell 33, 496-504.