MUTATIONS AND ALTERED EXPRESSION OF P16(INK4) IN HUMAN CANCER

Cell cycle arrest at the G(1) checkpoint allows completion of critical macromolecular events prior to S phase. Regulators of the G(1) checkpoint include an inhibitor of cyclin-dependent kinase, p16(INK4); two tumor-suppressor proteins, p53 and RB (the product of the retinoblastoma-susceptibility gene); and cyclin D1. Neither p16(INK4) nor the RB protein was detected in 28 of 29 tumor cell lines from human lung, esophagus, liver, colon, and pancreas. The presence of p16(INK4) protein is inversely correlated with detectable RB or cyclin D1 proteins and is not correlated with p53 mutations. Homozygous deletions of p16(INK4) were detected in several cell lines, but intragenic mutations of this gene were unusual in either cell lines or primary tumors. Transfection of the p16(INK4) cDNA expression vector into carcinoma cells inhibits their colony-forming efficiency and the p16(INK4) expressing cells are selected against with continued passage in vitro. These results are consistent with the hypothesis that p16(INK4) is a tumor-suppressor protein and that genetic and epigenetic abnormalities in genes controlling the G(1) checkpoint can lead to both escape from senescence and cancer formation.