The Molecular Balancing Act of p16 in Cancer and Aging

p16, located on chromosome 9p21.3, is lost among a cluster of neighboring tumor suppressor genes. Although it is classically known for its capacity to inhibit cyclin-dependent kinase (CDK) activity, p16 is not just a one-trick pony. Long-term p16 expression pushes cells to enter senescence, an irreversible cell-cycle arrest that precludes the growth of would-be cancer cells but also contributes to cellular aging. Importantly, loss of p16 is one of themost frequent events in human tumors and allows precancerous lesions to bypass senescence. Therefore, precise regulation of p16 is essential to tissue homeostasis, maintaining a coordinated balance between tumor suppression and aging. This review outlines the molecular pathways critical for proper p16 regulation and emphasizes the indispensable functions of p16 in cancer, aging, and human physiology that make this gene special. Mol Cancer Res; 12(2); 167–83. 2013 AACR.