Figure 9. Proposed mechanism by which Poldip2 promotes cell cycle progression.

Left: Passage 2. Poldip2 promotes progression though G1/S by preventing the accumulation of Cdk4/Cyclin D1 that occurs in Poldip2−/− cells. Poldip2 also limits the activation of p53 by phosphorylation at S20, which results in reduced Sirt1 expression. Reduced Sirt1 negatively regulates p53 by de-acetylation and reduces cell cycle progression. Right: Passage 4/5. Poldip2 activates the transcription of E2F target genes such as Cyclin A, Cdk1 and PCNA. These act to promote cell cycle progression. Poldip2 also reduces expression of the cell cycle inhibitor p21^CIP1. Reduced p21^CIP1 promotes cell cycle progression by relieving inhibition of the activity of Cyclin/Cdk complexes. We propose that Poldip2, like SV40 immortalization, inhibits p53 activity and sequesters Rb away from E2F, promoting cell cycle progression. Finally, Poldip2 inhibits autophagy, which results in increased growth.