Role of the ubiquitin ligase Fbw7 in cancer progression.

Fbw7 is a member of F-box family proteins, which constitute one subunit of Skp1, Cul1, and F-box protein (SCF) ubiquitin ligase complex. SCF(Fbw7) targets a set of well-known oncoproteins, including c-Myc, cyclin E, Notch, c-Jun, and Mcl-1, for ubiquitylation and degradation. Fbw7 provides specificity of the ubiquitylation of these substrate proteins via recognition of a consensus phosphorylated degron. Through regulation of several important proteins, Fbw7 controls diverse cellular processes, including cell-cycle progression, cell proliferation, differentiation, DNA damage response, maintenance of genomic stability, and neural cell stemness. As reduced Fbw7 expression level and loss-of-function mutations are found in a wide range of human cancers, Fbw7 is generally considered as a tumor suppressor. However, the exact mechanisms underlying Fbw7-induced tumor suppression is unclear. This review focuses on regulation network, biological functions, and genetic alteration of Fbw7 in connection with its role in cancer development.