Regulation of Thymidylate Synthase Gene Expression and Drug Response

Thymidylate synthase (TS) is a major target for anticancer drug action. Understanding of the mode of regulating TS expression is of great importance to developing strategies to reducing TS levels and activity, and inhibiting the enzyme with paramount efficacy. Over the years investigations of TS levels have alternatively produced evidence supporting the contributions of transcriptional or posttranscriptional regulation, as well as evidence for cell cycle phase-specific or phase-independent mechanisms in regulating TS levels. Most of the literature in this area concludes that TS is a cell cycle, S-phase-specific enzyme. However, as will be discussed, the data frequently rely on biological models that utilize questionable, although widely accepted, assumptions of biological validity. These models may not always be appropriate for generating generalized conclusions of the mechanism for regulationg TS levels. This chapter presents and overview of the key data concerning the regulation of TS gene expression with the perspective that much of the prevailing view that TS is an S-phase enzyme is incorrect. The iconoclastic view of the regulation of TS discussed in this chapter has its origins in the investigations of the rTS gene, a gene that overlaps the 3′-end of the TS gene and codes for an RNA that is partially complementary (antisense) to the TS mRNA and pre-mRNA and two proteins that may be responsible for controlling a large fraction of TS gene expression at the posttranscriptional through effects on TS pre-mRNA and protein stability.