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. 2013 Jan 25;14(2):2431–2448. doi: 10.3390/ijms14022431

Figure 2.

Figure 2

p53/p21/pRb/E2F and p16/pRb/E2F signaling pathway. The INK4a/ARF locus encodes both ARF (alternate reading frame) and p16 protein. ARF could stimulate p53 through inhibition and degradation of MDM2 (mouse double minute 2 homolog). Activated p53 transactivates p21, which, in turn, inhibits CDK2/cyclin E with the consequent inhibition of CDK2-dependent phosphorylation of Rb. Unphosphorylated Rb suppresses the function of the G1/S phase-promoting factor, E2F, and as a result, cells are subjected to proliferation arrest and DNA damage repair. Similarly, p16 can inhibit the CDK4-6/cyclin D complex thereby reducing Rb phosphorylation and subsequent downstream signal transduction pathways. Thus, cells will arrest in G1 phase and fail to complete the cell cycle. Bmi1, a polycomb group protein, is a transcriptional repressor of p16. Bim1 also has a potential inhibitory role on reactive oxygen species (ROS) production [33].