CDC4FBXW7

CDC4 and FBXW7 refer to orthologous F-box/WD40 repeat–containing proteins that serve as substrate adaptors in the Skp1-Cullin-F-box (SCF) ubiquitin ligase complex. In humans, the gene is named FBXW7 and encodes the WD40-containing F-box protein 7; in yeast and other species the ortholog is known as CDC4. The two names reflect evolutionary conservation rather than separate genes in the same organism.

The proteins contain an N-terminal F-box that binds Skp1 and a C-terminal WD40 propeller that recognizes phosphorylated substrates. As part of SCF E3 ligases, they recruit specific substrates for ubiquitination and subsequent proteasomal degradation, regulating processes such as cell cycle progression, differentiation, and signaling pathways.

Key substrates include cyclin E, c-Myc, the Notch1 intracellular domain, and c-Jun. By controlling the stability of these oncoproteins and transcription factors, FBXW7/CDC4 acts as a tumor suppressor. Mutations or loss of function disrupt substrate recognition, leading to accumulation of oncogenic proteins and increased cancer risk in affected tissues.

FBXW7 is among the most frequently mutated tumor suppressor genes in various cancers, including T-cell acute lymphoblastic leukemia, colorectal cancer, and endometrial cancer. Most pathogenic variants affect the WD40 repeats or regions required for substrate binding, reducing degradation efficiency and promoting tumorigenesis.

The FBXW7/CDC4 family is conserved across eukaryotes. The human gene FBXW7 has several splice variants, and recurring references to CDC4 in non-human species emphasize functional conservation of the SCF/FBXW7-CDC4 axis.