CUL2(Cullin 2) plays a crucial role in the ubiquitin-proteasome system, particularly in the regulation of protein degradation, which is vital for maintaining cellular homeostasis and controlling various biological processes such as the cell cycle, signal transduction, and responses to stress. CUL2 forms complexes with the von Hippel-Lindau (VHL) tumor suppressor protein and elongin B, creating VBC complexes that are structurally similar to the SCF (Skp1/CUL-1/F-box protein) complex. This interaction facilitates the targeted degradation of hypoxia-inducible factor (HIF), a key regulator of oxygen homeostasis, thereby influencing cellular responses to low oxygen levels. CUL2 modulates the stability of HIF and other substrates, underscoring CUL2′s importance in cancer biology and potential therapeutic interventions.