|Ph.D Student||Reinstein Eyal|
|Subject||Mechanisms of Recognition and Degradation of the Proto-|
Oncogene c-Myc and the Oncogene E7 by the
Ubiquitin Proteasome Proteolytic
|Department||Department of Medicine||Supervisor||? 18? Aaron Ciechanover|
The ubiquitin proteolytic system plays an important role in a broad array of basic cellular processes. Among these are regulation of cell cycle, modulation of the immune response, control of signal transduction pathways, development and differentiation. Degradation of a protein via the ubiquitin-proteasome pathway involves two successive steps : (1) covalent attachment of multiple ubiquitin molecules to the protein substrate, and (2) degradation of the tagged protein by the 26S proteasome and recycling of ubiquitin.
This work describes distinct mechanisms by which two different substrates are recognized and degraded by the ubiquitin system :
(1) The c-Myc proto-oncogene is a potent inducer of both cell proliferation and apoptosis. Deregulated expression of the gene has been detected in many tumor cell types. We have shown that the degradation of c-Myc protein is mediated by the ubiquitin system. Dissection of the mechanism involved in c-Myc degradation revealed that the high-risk human papillomavirus oncoprotein E6-16 stimulates conjugation and subsequent degradation of c-Myc. It is possible that in certain cells, E6-mediated targeting of c-Myc prevents Myc-induced apoptosis and thus ensures maintenance of viral infection.
(2) The E7 oncoprotein of the high risk human papillomavirus type 16 is a potent immortalizing and transforming agent. It served us as a model protein for studying a novel degradation pathway that involves N-terminal ubiquitination. We have shown that the E7 protein is a substrate for the ubiquitin system. Replacement of the two Lysine residues to Arginine, did not have any effect on ubiquitin-mediated conjugation and degradation of E7. As no lysine residues were available for ubiquitination, we suggest that the first ubiquitin residue is attached to the free N-terminal NH2 group.