Abstract
Absent expression of the cyclin dependent kinase-inhibitor, p16(INK4), is, observed in a wide range of primary human cancers. Although homozygous deletions and point mutations have been reported in a subset of these tumors, the molecular basis for absent p16(INK4) in other samples is unknown. We have examined 33 tumor cell lines and have shown that hypermethylation of a G:C-rich region within exon 1 of the CDKN2 gene was present in 100% of samples with wildtype RB expression and no detectable CDKN2 mutations. Treatment for at least 4 hours with the demethylating agent 5-aza 2'deoxycytidine, but not 5-azacytidine or 6-azacytidine, induces the prolonged expression of p16(INK4) protein in each of these samples following a discrete 24-48 hour lag period. Consistent with the hypothesis that hypermethylation of the CDKN2 gene is a tumor-specific mechanism for gene inactivation, we observed hypomethylation at the exon 1 site exclusively in tumor lines that expressed p16(INK4) or that had sustained inactivating point mutations within the CDKN2 open reading frame. These findings demonstrate a link between DNA methylation and the p16(INK4):RB tumor suppressor pathway.
Original language | English (US) |
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Pages (from-to) | 1211-1216 |
Number of pages | 6 |
Journal | Oncogene |
Volume | 11 |
Issue number | 6 |
State | Published - Jan 1 1995 |
Keywords
- 5-aza 2'deoxycytidine
- CDKN2
- Lung cancer
- Methylation
- p16(INK4)
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research