Modulation of the cell cycle by IGtranslocations.

A simplified diagram of the G₁- to S-phase transition. Genes that are deregulated as a result of IGtranslocation are shown in yellow. Cyclin D1/CDK6:Mitogenic signals result in transcriptional up-regulation of cyclin D1 and Akt-mediated inhibition of cyclin D1 degradation. Active cyclin D1-CDK4/6 (represented here by CDK6 for simplicity) phosphorylates Rb. The cell cycle inhibitors p27 (KIP1) and p21 (CIP1/WAF1) (represented by p27 [KIP1]) are required for assembly and activation of cyclin D-CDK4/6 complexes but mediate their inhibitory effects on the cell cycle through inactivation of cyclin E-CDK2. Overexpression of D-type cyclins or CDKs swings the equilibrium toward G₁- to S-phase transition by causing sequestration of p27 (KIP1) and p21 (CIP1/WAF1), allowing activation of cyclin E-CDK2. Rb is phosphorylated further by cyclin E-CDK2, promoting its dissociation from E2F, which then drives transcription of genes required for S-phase entry, including cyclin E. A feedback loop operates whereby cyclin E-CDK2 phosphorylates and promotes proteolytic degradation of p27 (KIP1).Myc: Myc mediates its effects on the cell cycle at least partly through transcriptional up-regulation of cyclin D1/D2, which, complexed with CDKs, sequester the cell cycle inhibitors p27 (KIP1) and p21 (CIP1/WAF1). NF-κB: NF-κB also promotes transition through the cell cycle through direct up-regulation of cyclin D1 transcription.BCL2: BCL2 appears to exert its inhibitory effects on the cell cycle through modulation of the p27 (KIP1) degradation pathway. Ub indicates ubiquitin; P, phosphorylation; D1, cyclin D1; E, cyclin E.