Ubiquitin

The regulation of protein stability via the ubiquitin–proteasome pathway is critical to the comprehension of the biomolecular basis of cancer development. However, ubiquitin modification of substrates signals many cellular processes (besides proteolysis) that are also important for cancer development. Interestingly, many breast cancer proteins studied by clinical researchers are involved in these specific ubiquitin pathways. These proteins include cyclins, CDK inhibitors and the SCF in cell cycle control, the breast and ovarian cancer suppressor BRCA1-BARD1, ErbB2/HER2/Neu and its ubiquitin ligase c-Cbl , as well as and the estrogen receptor and its target, Efp. One function of the ubiquitin–proteasome proteolysis pathway is to label proteins for rapid degradation. It consists of four enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), a ubiquitin ligase (E3) and the 26S proteasome [134]. E1 binds to and activates ubiquitin in an ATP-dependent manner through a thiolester bond and then transfers ubiquitin to an E2 enzyme. E2 then transfers ubiquitin to a lysine residue in the substrate via a terminal isopeptide bond through E3. E3 is a scaffold protein that bridges in the substrate and the ubiquitin-bound E2. The resultant covalent bonds of the ubiquitin ligations form polyubiquitinated conjugates that are quickly found and digested by the 26S proteasome.

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Last date updated on September, 2024