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doi: 10.1038/sj.cdd.4401692pmid: 16094394
Between the 1950s and 1980s, scientists were focusing mostly on how the genetic code is transcribed to RNA and translated to proteins, but how proteins are degraded has remained a neglected research area. With the discovery of the lysosome by Christian de Duve, it was assumed that cellular proteins are degraded within this organelle. Yet, several independent lines of experimental evidence strongly suggested that intracellular proteolysis is largely nonlysosomal, but the mechanisms involved remained obscure. The discovery of the ubiquitin–proteasome system resolved the enigma. We now recognize that degradation of intracellular proteins is involved in regulation of a broad array of cellular processes, such as cell cycle and division, regulation of transcription factors, and assurance of the cellular quality control. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of human disease, such as malignancies and neurodegenerative disorders, which led subsequently to an increasing effort to develop mechanism-based drugs.
doi: 10.1038/sj.cdd.4401702pmid: 16094395
Owing to the intensive research activity on protein synthesis, little attention was paid in the 1950s and 1960s to protein degradation. However, work by my group and others between 1970 and 1990 led to the identification of the ubiquitin-dependent degradation system. We found that this system contains three types of enzymes: E1 ubiquitin – activating enzyme, E2 ubiquitin – carrier enzyme and E3 ubiquitin – protein ligase. The sequential action of these enzymes leads to conjugation of ubiquitin to proteins and then in most cases to their degradation. This review briefly tells the story of how this pathway was discovered describing the main findings that during the years allowed us to draw the complex picture we have now.
doi: 10.1038/sj.cdd.4401710pmid: 16094396
My interest in protein breakdown as a research problem began in 1955. In 1963, when we relocated from Yale to the Institute for Cancer Research of Fox Chase, Philadelphia, nothing new was being reported. Here, I review how we get the ubiquitin proteasome system all together.
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