The INK4b-ARF-INK4a locus encodes three tumor suppressors, p15INK4b, ARF, and p16INK4a. Together, these factors constitute one the most important sources of cancer protection in mammals, equalled in importance only by p53. These tumor suppressors have taken on additional importance in the light of recent evidence that at least one product of the locus, p16INK4a, also contributes to the decline in the replicative potential of self-renewing cells with age. Thus, on the one hand, p16INK4a promotes longevity through its action as a potent tumor suppressor, while on the other hand the increased expression of p16INK4a with age reduces stem and progenitor cell proliferation, ultimately reducing longevity. In other words, p16INK4a appears to balance the need to prevent cancer against the need to sustain regenerative capacity throughout life. These observations suggest the provocative but unproven notion that mammalian aging results in part from the effectiveness of tumor suppressor proteins at preventing cancer.

Our group is investigating the role and molecular regulation of the INK4b-ARF-INK4a locus in the context of selfrenewal, proliferation and aging of hematopoietic stem cells in vitro and in vivo, with planned extension of these studies to cardiac stem cells. In parallel, we are developing tools for the study of the genetic and epigenetic mechanisms that regulate stem cells, and how these unique cells differentiate from a pluripotent to a more restricted state.