The human p19ARF protein encoded by the beta transcript of the p16INK4a gene is frequently lost in small cell lung cancer.
The p16IN4/CDKN2/MTS1 gene encodes two structurally different proteins: a cyclin-dependent kinase inhibitor called p16INK4a, which regulates retinoblastoma protein-dependent G1 arrest, and a cell cycle inhibitor designated p19ARF, which arrests cell growth in G1-S and also in G2-M. Whereas inactivation of p16INK4a has been described as a frequent event in lung cancer, the current function of p19ARF is still poorly understood. We have examined the expression of the human p19ARF (hp19ARF) 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 1beta and 2 of hp19ARF in those NE tumors with negative immunoreactivity, and a beta transcript was detected in the majority of them. Concomitant absence of hp19ARF and retinoblastoma proteins was frequently detected in high-grade NE lung tumors, whereas no relationship could be found between the status of hp19ARF and p53 proteins in those tumors. These results are consistent with an alternative growth suppressor function for hp19ARF in NE lung cancer that is distinct from that of p16INK4a. Moreover, the frequent uncoupling between the beta transcript and the hp19ARF protein suggests a novel mechanism of inactivation at the translational level.
Gazzeri
S
S
Groupe de Recherche sur le Cancer du Poumon, C.J.F. INSERM 97/01, Institut Albert Bonniot, La Tronche, France. Sylvie.Gazzeri@ujf-grenoble.fr
Della Valle
V
V
Chaussade
L
L
Brambilla
C
C
Larsen
C J
CJ
Brambilla
E
E
D018288:Carcinoma, Small Cell / Q000737:chemistry*; D002874:Chromosome Mapping; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis / Q000235:genetics*; D005091:Exons; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000737:chemistry; D008175:Lung Neoplasms / Q000737:chemistry*; D009687:Nuclear Proteins; D018807:Polymorphism, Single-Stranded Conformational; D011506:Proteins / Q000032:analysis* / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000032:analysis; D016160:Retinoblastoma Protein / Q000032:analysis; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2