Degrons in cancer

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Sci. Signal.  14 Mar 2017:
Vol. 10, Issue 470, eaak9982
DOI: 10.1126/scisignal.aak9982

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There are many cellular proteins that need to be eliminated quickly in response to changing conditions in or around the cells. Most of these proteins carry a short functional element in their sequence, called a degron. Degrons are typically composed of 6 to 10 amino acids and are generally located within flexible regions of proteins so that the degrons can easily interact with other proteins. E3 ubiquitin ligases bind to specific degrons, enabling the attachment of multiple copies of ubiquitin to target proteins. The ubiquitin chains are a molecular signal that directs the proteins to the proteasome, where the tagged proteins are chopped up into pieces and recycled. The correct removal of proteins is important for many biological processes, such as regulating transcription and controlling the major steps during cell division. Regulated protein degradation also turns off the activity of some proteins that are activated by transient external signals. The encounter between the E3 ligase and the degron determines whether a protein lives or dies. There are ~600 different E3 ligases that are encoded in the human genome. Each of these E3 ligases targets a different set of proteins and operates under a different condition. This ubiquitin-mediated protein degradation process is regulated at multiple levels. Defects in this system can cause systemic diseases, including cancer. This Review with 8 figures, 1 table, and 360 references describes how mutations that affect ubiquitin-mediated protein degradation system contribute to cancer.

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