Carcinogenesis, Vol 19, 567-573, Copyright © 1998 by Oxford University Press
J Dosch, M Christmann and B Kaina
To elucidate mechanisms involved in alkylating drug resistance, Chinese
hamster cells resistant to methylating agents have been generated upon
transfection with human DNA. Here it is shown that these Chinese hamster
ovary (CHO) variants exhibit the tolerance phenotype: they are
alkyltransferase deficient (Mex-), cross-resistant to 6-thioguanine,
exhibit reduced G-T binding (MutS alpha) activity and express the mismatch
repair protein MSH2 at a significantly lower level than the corresponding
control. By comparing wild-type cells with different tolerant strains that
show gradual differences in resistance to methylating agents, it was shown
that both the G-T binding activity and the amount of MSH2 protein inversely
correlates with the level of methylating drug resistance. Although the
tolerant cell variants analysed express MSH2 at a significantly lower level
than the wild- type, MSH2 mRNA expression was not impaired. Furthermore,
MSH2 promoter activity was not reduced upon transient transfection into
tolerant cells. The results indicate that quantitative differences in
expression of components of mismatch repair do exist in mammalian cells
that affect cell survival upon methylation. It appears that post-
transcriptional mechanisms are involved in regulation of MSH2 expression.
ARTICLES
Mismatch G-T binding activity and MSH2 expression is quantitatively related to sensitivity of cells to methylating agents
Division of Applied Toxicology, Institute of Toxicology, University of Mainz, Germany.
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