title: Negative regulation of NEDD8 conjugation pathway by novel molecules and agents for anticancer therapy.
abstract: 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.
authors.affiliation: Department of Urology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abenoku, Osaka 545-8585, Japan. tomoaki826@msic.med.osaka-cu.ac.jp
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Nakatani
authors.forename: Tetsu
authors.initials: T
authors.lastname: Kamitani
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003517:Cyclopentanes / Q000627:therapeutic use*; D006801:Humans; D000075687:NEDD8 Protein; D009369:Neoplasms / Q000188:drug therapy*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects*; D011743:Pyrimidines / Q000627:therapeutic use*; D014452:Ubiquitins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D003517:Cyclopentanes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; D014452:Ubiquitins; D046988:Proteasome Endopeptidase Complex; C539933:pevonedistat