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 and inflammatory responses, control of signal transduction pathways, development and differentiation. These complex processes are controlled via specific degradation of a single or a subset of proteins. Degradation of a protein by the ubiquitin system involves two successive steps, conjugation of multiple moieties of ubiquitin and degradation of the tagged protein by the 26S proteasome. An important question concerns the identity of the mechanisms that underlie the high degree of specificity of the system. Substrate recognition is governed by a large family ubiquitin ligases that recognize the substrates, bind them and catalyze/facilitate their interaction with ubiquitin. BioEssays 22:442±451, 2000.
Cellular proteins are in a dynamic state maintained by synthesis and degradation. The ubiquitin proteolytic pathway is responsible for the degradation of the bulk of cellular proteins including short-lived, regulatory, and misfolded/denatured proteins. Ubiquitin-mediated proteolysis involves covalent attachment of multiple ubiquitin molecules to the protein substrate and degradation of the targeted protein by the 26S proteasome. Recent understanding of the molecular mechanisms involved provides a framework to understand a wide variety of human pathophysiological states as well as therapeutic interventions. This review focuses on the response to hypoxia, inflammatory diseases, neurodegenerative diseases, and muscle-wasting disorders, as well as human papillomaviruses, cervical cancer and other malignancies.
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