Carcinogenesis, Vol 18, 115-120, Copyright © 1997 by Oxford University Press
SA Belinsky, DS Swafford, SK Middleton, CH Kennedy and J Tesfaigzi
Recent allelotyping of chemical-induced lung tumors in hybrid mice has
detected loss of heterozygosity on chromosome 4 in a region involving the
interferon-alpha (IFN-alpha gene cluster that is syntenic to human
chromosome 9p21-22, the location of the p16INK4a (p16) and p15INK4b (p15)
tumor suppressor genes. The purpose of the current investigation was to
characterize the expression of p16 and p15 in lung tumors and tumor-derived
cell lines induced in A/J mice by exposure to the tobacco- specific
nitrosamine, 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK). Expression
of p16 and p15 was detected in all primary lung tumors; however, levels of
expression of p16 differed by up to 15-fold between tumors. This is the
first study to note a marked difference in the expression of the p16 gene
in primary lung tumors. The apparent low levels of expression seen in
approximately half of the tumors was not attributed to deletion, mutation
or methylation of the p16 gene. Conversely, the high levels of p16
expression were not the result of effects on the retinoblastoma gene (Rb)
or cyclin D1 proteins but most likely in response to a dysfunction
elsewhere within this pathway. In contrast to the detection of p16
expression in primary tumors, this gene was deleted in all four cell lines.
Three of four cell lines also showed loss of the p15 gene. Mapping of these
homozygous deletions on chromosome 4 revealed that the p16 gene resides
near the D4MIT77 marker, which is located approximately 12 cM proximal to
the IFN-alpha gene cluster, thereby implicating the p16 gene as one of the
targets within the allelic deletions detected previously in primary lung
tumors from hybrid mice.
ARTICLES
Deletion and differential expression of p16INK4a in mouse lung tumors
Inhalation Toxicology Research Institute, Albuquerque, NM 87185, USA.
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