《《2016-Cell-The regulation of INK4ARF in cancer and aging》.pdf

Leading Edge Review The Regulation of INK4/ARF in Cancer and Aging 1 1, William Y. Kim and Norman E. Sharpless * 1Departments of Medicine and Genetics, The University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA *Contact: nes@med.unc.edu DOI 10.1016/j.cell.2006.10.003 Loss of the INK4a/ARF/INK4b locus on chromosome 9p21 is among the most frequent cytogenetic events in human cancer. The products of the locus—p15INK4b, p16INK4a, and ARF—play widespread and independent roles in tumor suppression. Recent data also suggest that expression of p16INK4a induces an age-dependent decrease in the proliferative capacity of certain tissue-specific stem cells and unipotent progenitors. Here, we discuss the regulation and role of p16INK4a, ARF, and p15INK4b in cancer and aging. Regulated cellular proliferation is required for mamma- common second and third exon. Although exons 2 and 3 lian homeostasis, but uncontrolled proliferation is the are shared by p16INK4a and ARF, the proteins are encoded hallmark of cancer. Therefore, an important question in in alternative reading frames. As a consequence p16INK4a cancer biology is how a tumor suppressor protein dis- and ARF are not isoforms and do not share any amino tinguishes malignant from physiological growth? This is acid homology (Figure 1). no mean feat. Physiologic growth can have many of the The INK4 class of cell-cycle inhibitors p15INK4b, p16INK4a, properties associated with the worst malignancies: it p18INK4c, and p19INKd (the latter not to be confused with ARF can be rapid, disordered, unexpected, and invasive (for p19 ) are homologous inhibitors of the