The ubiquitin system: pathogenesis of human diseases and drug targeting.
With the many processes and substrates targeted by the ubiquitin pathway, it is not surprising to find that aberrations in the system underlie, directly or indirectly, the pathogenesis of many diseases. While inactivation of a major enzyme such as E1 is obviously lethal, mutations in enzymes or in recognition motifs in substrates that do not affect vital pathways or that affect the involved process only partially may result in a broad array of phenotypes. Likewise, acquired changes in the activity of the system can also evolve into certain pathologies. The pathological states associated with the ubiquitin system can be classified into two groups: (a) those that result from loss of function-mutation in a ubiquitin system enzyme or in the recognition motif in the target substrate that lead to stabilization of certain proteins, and (b) those that result from gain of function-abnormal or accelerated degradation of the protein target. Studies that employ targeted inactivation of genes coding for specific ubiquitin system enzymes and substrates in animals can provide a more systematic view into the broad spectrum of pathologies that may result from aberrations in ubiquitin-mediated proteolysis. Better understanding of the processes and identification of the components involved in the degradation of key regulatory proteins will lead to the development of mechanism-based drugs that will target specifically only the involved proteins.
Ciechanover
Aaron
A
Tumor and Vascular Biology Research Center, the Rappaport Family Institute for Research in the Medical Sciences, and the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel. c_tzachy@netvision.net.il
Schwartz
Alan L
AL
D000818:Animals; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D015195:Drug Design; D006801:Humans; D007107:Immune System / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D018908:Muscle Weakness / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D025801:Ubiquitin / Q000502:physiology*
D008565:Membrane Proteins; D025801:Ubiquitin