Tumor cells frequently promote the dysregulation of the cell cycle and escape from apoptotic cell death triggered by a number
of cellular stresses. Programmed proteolytic degradation of regulatory proteins via the ubiquitin-proteasome pathway is crucial for homeostasis
of numerous biological processes. Disruption of this system is one of the factors that promote aberrant cell-proliferation. The
small ubiquitin-like protein, NEDD8, has been identified as a fundamental regulator of the activity of the E3 ubiquitin ligases called the
SCF complex (consisting of Skp-1, cullin, and F-box protein) or CRL (cullin-RING ubiquitin ligase) which control a final step in ubiquitination
of diverse substrates associated with cancer biology. The ubiquitin ligase activity of the SCF complex requires NEDD8 to covalently
bind to cullins. To a large extent, exploring the negative regulation system of the NEDD8 pathway is expected to lead to the development
of novel anticancer targets. This review focuses on the NEDD8 negative regulation system including chemical compounds such
as MLN4924 and protein molecules (e.g. COP9 signalosome, CAND1, inactive mutant of Ubc12 and NUB1/NUB1L) and clarifies possible
strategies for targeting the NEDD8 cascade in cancer cells.
Keywords: Ubiquitination, SCF complex, NEDD8, MLN4924, COP9 signalosome, CAND1, NUB1/NUB1L.
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