Aberrations in the MTS1 tumor suppressor locus in oral squamous cell carcinoma lines preferentially affect the INK4A gene and result in increased cdk6 activity.
The signal transduction pathway regulated by the retinoblastoma tumor suppressor protein, pRB, is abrogated in the majority of human cancers. Using a series of cell lines derived from oral squamous cell carcinomas (SCCs) that were not subjected to radiation or chemotherapy treatment, we detected specific hyperactivity of cyclin dependent kinase (cdk) 6 but not cdk4. Subcellular localization studies showed a predominant nuclear localization of cdk6, demonstrating that this kinase was biologically active. The molecular basis for this aberration are mutations in the MTS1 locus of chromosome 9p21. This locus encodes two partially overlapping genes, the cdk inhibitor p16(ink4a), and p14(ARF), an inhibitor of mdm2-mediated degradation of p53. Our analysis demonstrates that the mutations of the MTS1 locus in oral SCC specifically target expression of the p16(ink4a) gene but less frequently affect p14(ARF). These results suggest that hyperactivity of cdk6 represents a distinct mechanism for pRB inactivation in oral SCC.
Piboonniyom
Siribang-on
SO
Department of Oral Medicine and Diagnostic Sciences, Harvard School of Dental Medicine, Boston, MA 02115, USA.
Timmermann
Stefanie
S
Hinds
Philip
P
Münger
Karl
K
D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D018844:Cyclin-Dependent Kinases; D019942:Genes, p16; D006801:Humans; D009062:Mouth Neoplasms / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D025803:Tumor Suppressor Protein p14ARF; D017346:Protein Serine-Threonine Kinases; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases