The p14-p53-p21 pathway and the p16-Rb signaling pathways involved in fibroblast senescence. (a) Activated p53 induces expression of p21. The protein p21 binds to cyclin-dependent kinase 2 (CDK2), which in turn impedes CDK2 from complexing with Cyclin E and Cyclin A. Since the CDK2-Cyclin E/A complexes are required for DNA replication to begin, p21 effectively stops cell replication. Mdm2 is a strong antagonist of p53. It not only prevents production of new p53 through transcriptional inhibition, but also exports active p53 from the nucleus and targets it for proteolytic destruction through ubiquitination. The tumor suppressor protein p14 works to upregulate p53 by inhibiting Mdmd2 [16]. (b) While in its unphosphorylated state, Rb sequesters the transcription factor (E2F) responsible for initiating DNA replication. Unphosphorylated Rb also induces the formation of SAHF, which prevents free E2F from complexing with DNA. When cyclin-dependent kinase 4 (CDK4) complexes with cyclin D, it is able to phosphorylate Rb, thus releasing E2F and allowing DNA replication to occur. The protein p16 works as a tumor suppressor by preventing CDK4 from complexing with cyclin D.
