Alterations of p14(ARF), p53, and p73 genes involved in the E2F-1-mediatedapoptotic pathways in non-small cell lung carcinoma

Overexpression of E2F-1 induces apoptosis by both a p14(ARF)-p53- and a p73 -mediated pathway. p14(ARF) is the alternate tumor suppressor product of th e INK4a/ARF locus that is inactivated frequently in lung carrinogenesis, Be cause p14(ARF) stabilizes p53, it has been proposed that the loss of p14(AR F) is functionally equivalent to a p53 mutation. We have tested this hypoth esis by examining the genomic status of the unique exon Ip of p14(ARF) in 5 3 human cell lines and 86 primary non-small cell lung carcinomas and correl ated this with previously characterized alterations of p53, Homozygous dele tions of p14(ARF) were detected in 12 of 53 (23%) cell lines and 16 of 86 ( 19%) primary tumors. A single cell line, but no primary tumors, harbored an intragenic mutation. The deletion of p14(ARF) was inversely correlated wit h the loss of p53 in the majority of cell lines (P = 0.02), but this relati onship was not maintained among primary tumors (P = 0.5). E2F-1 can also in duce p73 via a p53-independent apoptotic pathway, Although we did not obser ve inactivation of p73 by either mutation or DNA methylation, haploinsuffic iency of p73 correlated positively with either p14(ARF) Or p53 mutation or both (P = 0.01) in primary non-small cell lung carcinomas. These data are c onsistent with the current model of p14(ARF) and p53 interaction as a compl ex network rather than a simple linear pathway and indicate a possible role for an E2F-1-mediated failsafe, p53-independent, apoptotic pathway involvi ng p73 in human lung carcinogenesis.