p19INK4D and cell death.

INK4 proteins are members of a family of cyclin-dependent kinase (CDK) inhibitors that function in G(1) to block the activity of CDKs 4 and 6. While they share clear structural similarities, numerous studies have shown that INK4 proteins differ in their expression patterns during development and in the adult, and have differing roles in tumor suppression. A recent study from our laboratory showed that expression of the gene encoding p19(INK4D) is induced by the hormonal form of vitamin D(3) and by retinoids, both of which signal through related nuclear receptor transcription factors. Although vitamin D(3) and retinoids have distinct developmental and physiological functions, both regulate the cell cycle and have been shown to have chemopreventive effects in a range of studies. Induction of p19(INK4D) expression contributed to cell cycle arrest by both ligands. However, knockdown of p19(INK4D) rendered cells sensitive to autophagic cell death, a remarkable phenotype given the hyperproliferative responses to loss of other INK4 proteins. We discuss the relevance of our studies and recent findings of others to the cell death observed in p19(INK4D)-deficient animals and to a possible role for p19(INK4D) induction in chemoprevention.