Regulation of NFkB, E2F/Rb and p53/p21 pathways of cell cycle arrest by PIs. Proteasome inhibitors block the degradation of IĸB, an inhibitor of NFĸB via proteasome. This causes the accumulation of NF-ĸB in cytosol and represses its transcriptional activity which further inhibits CyclinD1 expression. Decreased Cyclin D1 level terminates its binding to CDK4, which in turn fails to hypo-phosphorylate the Rb protein. Once hypo-phosphorylation of Rb protein is ceased its hyper-phosphorylation by Cyclin E/ CDK2 complex is abrogated and its dissociation from E2F and proteasomal degradation is also inhibited. Undissociated E2F fails to express CyclinA genes and genes involved in DNA synthesis and S phase progression. On the other hand, proteasome inhibitors also inhibit mdm2 mediated degradation of p53 protein leading to the reactivation of its transcriptional activity. p53 reactivation increases p21 expression, a CKI, which inhibit cyclin E/ CDK2 complex ceasing G1 phase progression. However p21 also is known to inhibit cyclin B/ CDK1 complex causing G2/M arrest. Proteins like APC and cdc25 family members are also key players in the sG2/M phase of cell cycle but their modulation by PIs still remains unclear.