CACUL1 and cancer: Given the opposite mechanistic effects of MLN4924 and CSN5i-3 on the NEDDylation status of CRLs (MLN4924: inhibition of cullin NEDDylation and CRL ubiquitin ligase activity; CSN5i-3: accumulation of cullins in their NEDDylated, active state), the effectiveness of both drugs on cancer cell behavior is at first sight surprising, but can be explained by the different susceptibility of various F box proteins/substrate receptor modules (SRMs) to CRL auto-ubiquitination activity [57].