Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6. This inhibits their ability to interact with cyclins D and to phosphorylate the retinoblastoma protein (By similarity). Heterodimer with CDK4 or CDK6. Predominamt P16 complexes contained CDK6. Interacts with CDK4 (both 'T-172'-phosphorylated and non-phosphorylated forms); the interaction inhibits cyclin D-CDK4 kinase activity. Interacts with ISCO2 (By similarity). Isoform 1 and isoform tumor suppressor ARF arise due to the use of two alternative first exons joined to a common exon 2 at the same acceptor site but in different reading frames, resulting in two completely different isoforms. Expressed predominantly in lung and testis. In the testis, restricted to germ cells in the seminiferous epithelium. Not detected in premeiotic spermatogonia but high levels found in postmeiotic spermatids. In primary tumors, low levels detected in melanocytic hyperplasias. Higher levels found in non-metastatic and metastatic melanomas. Produced by alternative initiation at Met-35 of isoform 1. Belongs to the CDKN2 cyclin-dependent kinase inhibitor family. The proteins described here are encoded by the gene CDKN2A, but are completely unrelated in terms of sequence and function to tumor suppressor ARF (AC O77618) which is encoded by the same gene.