Ubiquitin-dependent signaling: The role of ubiquitination in the response of cells to their environment.

The response of a cell to its external environment requires rapid and signi ficant alteration of protein amount, localization and/or function. This reg ulation involves a complex combination of processes that control synthesis, localization and degradation. Ail of these processes must be properly regu lated and are often interrelated. Intracellular proteolysis is largely acco mplished by the ubiquitin-dependent system and has been shown to be require d for growth control, cell cycle regulation, receptor function, development and the stress response. Substrates subject to regulated degradation by th is system include cyclins and cyclin-dependent kinase inhibitors, tumor sup pressors, transcription factors and cell surface receptors, In addition, pr oteins that are damaged by oxidation or that are improperly folded or local ized are substrates whose degradation by this system often leads to antigen presentation on the surface of the cell in the context of Class I major hi stocompatibility complex molecules. A very large body of work in the last f ifteen years has shown that degradation by this system requires the covalen t attachment of a small protein called ubiquitin and that this modification serves to direct target proteins for degradation by a 26S proteolytic part icle, the proteasome. Thus, the attachment of the ubiquitin domain is of vi tal importance in regulating normal growth and differentiation, as well as in defending against cellular damage caused by xenobiotics, environmental i nsults, infection and mutation. This review focuses on the role of ubiquiti nation in the cellular signaling pathways that deal with these external inf luences.