VHL as a tumor suppressor mediates many cellular processes due to its multi-functional role, in which interacted with HIF signaling is the most notably physiological event that VHL binds to Elongin B, Elongin C, Cul2, and Rbx1 proteins forming E3 ligase, leading to HIF-α degradation inhibiting tumor progression [306]. The gene discussed is CUL2; the disease is neoplasm.