In late 1993 and early 1994, two distinct lines of research converged on a new tumor suppressor gene located on human chromosome 9p21. The órst report was of the existence of a 16-kDa protein that became associated with cyclin dependent kinases (CDKs) when human diploid óbroblasts were transformed by SV40 virus [538]. The interaction with CDK4 was exploited to isolate the corresponding cDNA in a yeast two-hybrid screen and it quickly became apparent that the 16-kDa protein, dubbed p16INK4, acted as an inhibitor of CDK4 [439]. Given the presumed role of CDK4 as a positive regulator of cell cycle progression (see below), any inhibitory protein could be viewed as a potential tumor suppressor, but almost before the chromosomal location of the gene was determined [350], two other groups had separately isolated the corresponding genomic DNA in a classical positional cloning exercise aimed at identifying a melanoma susceptibility gene and suspected tumor suppressor on chromosome 9p21 [216,338]. From these latter studies, additional names were coined: MTS1 formultiple tumor suppressor'and CDK4I, forCDK4-inhibitor'. Yet another nomenclature, CDKN2, was adopted for the locus designation in the human genome project. Perhaps because CDKN2 is more difficult to pronounce, much