biquitin-mediated degradation of intracellular proteins is involved in the regulation of many basic cellular processes including cell cycle progression, transcriptional activation, growth and development, differentiation, apoptosis, membrane receptor modulation and DNA repair. Research in our laboratory focuses on regulated activation and degradation of transcriptional regulators such as the major immune system modulator NF-kB, the tumor suppressor p53, and MyoD, the major transcriptional regulator involved in muscle differentiation. Interesting in particular is the case of NF-kB. The regulator is activated in a two-step mechanism. Initially, the precursor protein p105 is cleaved to generate the p50 active subunit. This is a rare case in which the target molecule is processed in a limited manner rather then destroyed completely. p50 then associates with p65 to generate the active heterodimeric transcriptional activator that is sequestered inactive in the cytosol following generation of a heterotrimeric complex with the inhibitor IkBa. Signal-induced phosphorylation of the inhibitor on specific Ser residues leads to its rapid degradation. This allows translocation of the active p50!p65 activator into the nucleus where it initiates specific transcription. We have reconstituted - both in vitro and in vivo - the activation cascade of NF-kB, identified the signals that protect p105 from complete destruction, and characterized the enzymes, the ubiquitin-conjugating enzymes, E2s, and ligases, E3s, involved in the activation process. We are currently studying their mode of regulation in a biological context.

Representative Publications:

Breitschopf K., Bengal E., Ziv T., Admon A. and Ciechanover A. (1998). A Novel Site for Ubiquitination: The N-Terminal Residue and Not Internal Lysines of MyoD is Essential for Conjugation and Degradation of the Protein. EMBO J.; 17, 5964-5973.

Orian A., Gonen H., Bercovich B., Fajerman I., Eytan E., Israel A., Mercurio F., Iwai K, Schwartz A.L. and Ciechanover A. (2000). SCF-$-TrCP Ubiquitin Ligase-Mediated Processing of NF-6B p105 Requires Phosphorylation of its C-Terminus by I6B Kinase. EMBO J.; 19, 2580-2591.

Cohen S., Orian A. and Ciechanover A. (2001). Processing of p105 is Inhibited by Docking of p50 Active Subunits to the Ankyrin Repeat Domain, and Inhibition is Alleviated by Signaling via the C-Terminal Phosphorylation/Ubiquitin-Ligase Binding Domain. J. Biol. Chem.; 276, 26769-26776.