In vitro models of carcinogenesis: expression of recessive genes by chromosomal mutations.
There has been considerable recent interest in the mechanisms by which recessive mutations involving cancer genes may be expressed. We have developed an in vitro model to study this phenomenon in an endogenous autosomal gene in human cells. We have analyzed the molecular structural changes that lead to loss of heterozygosity at the thymidine kinase (tk) locus. The results indicate that expression of a recessive allele frequently occurs by loss of heterozygosity at that locus. Over 90% of spontaneous mutants at the tk locus arose by allele loss. The fraction of induced mutants that arose by this mechanism depended upon the inducing agent. Loss of the active tk allele was often accompanied by loss of linked genetic loci on the long arm of chromosome 17. These results suggest that large-scale chromosomal mutations resulting from events such as deletion or mitotic recombination may be an important mechanism for the expression of activated or mutated recessive genes in human cells. Such recessive mutations could involve oncogenes or other growth regulatory genes important in carcinogenesis.
Kresge Center for Environmental Health, Harvard School of Public Health, Boston, MA 02115.
J B
JB
Little
D002455:Cell Division; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17; D005808:Genes, Recessive; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D013937:Thymidine Kinase / Q000235:genetics; D014407:Tumor Cells, Cultured
D013937:Thymidine Kinase