5/2/2023 0 Comments Jstock jcpFBXW7α is ubiquitously expressed in the majority of proliferating cells and performs most of the known FBXW7 functions. FBXW7α is localized in the nucleoplasm, FBXW7β is cytoplasmic, and FBXW7γ is nucleolar. These isoforms have distinct cellular localizations restricting interactions with specific partners and their functions. In mammalian cells there are three FBXW7 isoforms: FBXW7α, FBXW7β, and FBXW7γ, which differ in their 5’-UTR and N-terminal coding regions. These F-box proteins, including FBXW7, are responsible for recognizing and binding to phosphorylated substrates regulating their turnover. The SCF complex is composed of four subunits – Skp1, Cul-1 (Cullin/Cdc53), and Rbx1 proteins – and a fourth component consisting of a variable F-box protein that determines substrate specificity. The SCF complex is an E3-ubiquitin ligase that ubiquinates proteins and triggers proteasome degradation. In the following sections, we will discuss the regulation of FBXW7, its role in oncogenesis, and the clinical implications and prognostic value of loss of function of FBXW7 in human cancers.įBXW7 is a member of the F-box protein family, which is part of the Skp1-Cdc53/Cullin-F-box-protein complex (SCF/β-TrCP). In addition to genetic mutations, other mechanisms involving microRNA, long non-coding RNA, and specific oncogenic signaling pathways can inactivate FBXW7 functions in cancer cells. Genetic profiles of human cancers based on high-throughput sequencing have revealed that FBXW7 is frequently mutated in human cancers. Consistent with the tumor suppressor role of FBXW7, it is located at chromosome 4q32, a genomic region deleted in more than 30% of all human cancers (Spruck CH et al., Cancer Res 62:4535-9, 2002). FBXW7 controls proteasome-mediated degradation of oncoproteins such as cyclin E, c-Myc, Mcl-1, mTOR, Jun, Notch and AURKA. FBXW7 is a critical tumor suppressor and one of the most commonly deregulated ubiquitin-proteasome system proteins in human cancer. F-box and WD repeat domain containing 7 (FBXW7), also known as Sel10, hCDC4 or hAgo, is a member of the F-box protein family, which functions as the substrate recognition component of the SCF E3 ubiquitin ligase. The ubiquitin-proteasome system (UPS) is involved in multiple aspects of cellular processes, such as cell cycle progression, cellular differentiation, and survival (Davis RJ et al., Cancer Cell 26:455-64, 2014 Skaar JR et al., Nat Rev Drug Discov 13:889-903, 2014 Nakayama KI and Nakayama K, Nat Rev Cancer 6:369-81, 2006).
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