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Nobel Laureate Aaron Ciechanover: "Intracellular proteolysis and the ubiquitin system: From the backyard of biological research to the forefront of the patient bed"

Wann 22.06.2010
von 17:15 bis 18:15
Wo Chemistry Lecture Hall, Albertstr. 21, 79104 Freiburg
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Why Our Proteins Have to Die so We shall Live or The Ubiquitin Proteolytic System - From Basic Mechanisms and onto Disease Mechanisms and Drug Development

Between the 50s and 80s, most studies in biomedicine focused on the central dogma - the translation of the information coded by DNA to RNA and proteins. Protein degradation was a neglected area, considered to be a non-specific, dead-end process. While it was known that proteins do turn over, the high specificity of the process - where distinct proteins are degraded only at certain time points, or when they are not needed any more, or following denaturation/misfolding when their normal and active counterparts are spared - was not appreciated. The discovery of the lysosome by Christian de Duve did not significantly change this view, as it was clear that this organelle is involved mostly in the degradation of extracellular proteins, and their proteases cannot be substrate-specific. The discovery of the complex cascade of the ubiquitin solved the enigma. It is clear now that degradation of cellular proteins is a highly complex, temporally controlled, and tightly regulated process that plays major roles in a variety of basic cellular processes such as cell cycle and differentiation, communication of the cell with the extracellular environment and maintenance of the cellular quality control. With the multitude of substrates targeted and the myriad processes involved, it is not surprising that aberrations in the pathway have been implicated in the pathogenesis of many diseases, certain malignancies and neurodegeneration among them, and that the system has become a major platform for drug targeting.

 

Intracellular proteolysis and the ubiquitin system: From the backyard of biological research to the forefront of the patient bed

The Nobel Prize in Chemistry for 2004 was shared between three scientists who have made fundamental discoveries concerning how cells regulate the breakdown of intracellular proteins with extreme specificity as to target, time and space. Aaron Ciechanover, Avram Hershko and Irwin Rose together discovered ubiquitin-mediated proteolysis, a process where an enzyme system tags unwanted proteins with many molecules of the 76-amino acid residue protein ubiquitin. The tagged proteins are then transported to the proteasome, a large multisubunit protease complex, where they are degraded. Numerous cellular processes regulated by ubiquitin-mediated proteolysis include the cell cycle, DNA repair and transcription, protein quality control and the immune response. Defects in this proteolysis have a causal role in many human diseases, including a variety of cancers.