Alterations of p14 ARF , p53 , and p73 Genes Involved in the E2F-1-mediated Apoptotic 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 the INK4a/ARF locus that is inactivated frequently in lung carci- nogenesis. Because p14 ARF stabilizes p53 , it has been proposed that the loss of p14 ARF is functionally equivalent to a p53 mutation. We have tested this hypothesis by examining the genomic status of the unique exon 1 b of p14 ARF in 53 human cell lines and 86 primary non-small cell lung carcinomas and correlated this with previously characterized alterations of p53 . Homozygous deletions 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 with the loss of p53 in the majority of cell lines ( P 5 0.02), but this relationship was not maintained among primary tumors ( P 5 0.5). E2F-1 can also induce p73 via a p53 -independent apoptotic pathway. Although we did not observe inactivation of p73 by either mutation or DNA methylation, haploinsufficiency of p73 correlated positively with either p14 ARF or p53 mutation or both ( P 5 0.01) in primary non-small cell lung carcinomas. These data are consistent with the current model of p14 ARF and p53 interaction as a complex network rather than a simple linear pathway and indicate a possible role for an E2F-1 -mediated failsafe, p53 -independent, apoptotic pathway involving p73 in human lung carcinogenesis.