A. Okamoto et al., MUTATIONS AND ALTERED EXPRESSION OF P16(INK4) IN HUMAN CANCER, Proceedings of the National Academy of Sciences of the United Statesof America, 91(23), 1994, pp. 11045-11049
Cell cycle arrest at the G(1) checkpoint allows completion of critical
macromolecular events prior to S phase. Regulators of the G(1) checkp
oint include an inhibitor of cyclin-dependent kinase, p16(INK4); two t
umor-suppressor proteins, p53 and RB (the product of the retinoblastom
a-susceptibility gene); and cyclin D1. Neither p16(INK4) nor the RB pr
otein was detected in 28 of 29 tumor cell lines from human lung, esoph
agus, 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) w
ere detected in several cell lines, but intragenic mutations of this g
ene 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 c
onsistent with the hypothesis that p16(INK4) is a tumor-suppressor pro
tein and that genetic and epigenetic abnormalities in genes controllin
g the G(1) checkpoint can lead to both escape from senescence and canc
er formation.