RETINOBLASTOMA-PROTEIN-DEPENDENT CELL-CYCLE INHIBITION BY THE TUMOR-SUPPRESSOR P16

D-TYPE cyclins, in association with the cyclin-dependent kinases Cdk4 or Cdk6, promote progression through the G1 phase of the cell cycle(1- 6) by phosphorylating the retinoblastoma protein (RB)(7,8). The activi ties of Cdk4 and Cdk6 are constrained by inhibitors(9-12) such as p16, the product of the CDKN2 gene on human chromosome 9p21 (refs 12-14). The frequent deletion or mutation of CDKN2 in tumour cells suggests th at p16 acts as a tumour suppressor. We show that wild-type p16 arrests normal diploid cells in late G1, whereas a tumour-associated mutant o f p16 does not. Significantly, the ability of p16 to induce cell-cycle arrest is lost in cells lacking functional RB, including primary fibr oblasts from Rb--/- mouse embryos. Thus, loss of p16, overexpression o f D-cyclins and loss of RB have similar effects on G1 progression, and may represent a common pathway to tumorigenesis.