The progression of cells through the cell cycle is regulated by a family of proteins designated cyclin-dependent kinases (Cdks). Sequential activation of individual members of this family and their consequent phosphorylation of critical substrates, promote orderly progression through the cell cycle. The protein p16INK4A, identified as a negative regulator of the cell cycle, has been shown to bind to and inhibit the activity of the Cdk4/cyclin D complex. p19 ARF, which is unrelated to p16, arises from transcription of an alternative reading frame of the p16 gene. Like p16, p19 ARF has been shown to induce cell cycle arrest. Mice lacking p19 ARF but expressing functional p16 have been shown to develop tumors early in life. Further studies have indicated that p19 ARF may be disrupted in a large percentage of human T cell acute lymphoblastic leukemias.
