The Human p19^ARF Protein Encoded by the β Transcript of the p16^INK4a Gene Is Frequently Lost in Small Cell Lung Cancer¹

The p16^INK4/CDKN2/MTS1 gene encodes two structurally different proteins: a cyclin-dependent kinase inhibitor called p16^INK4a, which regulates retinoblastoma protein-dependent G₁ arrest, and a cell cycle inhibitor designated p19^ARF, which arrests cell growth in G₁-S and also in G₂-M. Whereas inactivation of p16^INK4a has been described as a frequent event in lung cancer, the current function of p19^ARF is still poorly understood. We have examined the expression of the human p19^ARF (hp19^ARF) protein in a large series of lung cancers using immunohistochemistry and showed that the protein was more frequently lost in high-grade neuroendocrine (NE) lung tumors (large cell NE carcinoma and small cell lung carcinoma; 51 of 78, 65%) than it was in non-small cell lung cancer (25 of 101, 25%). No deleterious mutation was found in exons 1β and 2 of hp19^ARF in those NE tumors with negative immunoreactivity, and a β transcript was detected in the majority of them. Concomitant absence of hp19^ARF and retinoblastoma proteins was frequently detected in high-grade NE lung tumors, whereas no relationship could be found between the status of hp19^ARF and p53 proteins in those tumors. These results are consistent with an alternative growth suppressor function for hp19^ARF in NE lung cancer that is distinct from that of p16^INK4a. Moreover, the frequent uncoupling between the β transcript and the hp19^ARF protein suggests a novel mechanism of inactivation at the translational level.