Thymidylate Synthase as an Oncogene: A Novel Role for an Essential DNA Synthesis Enzyme

Cancer Cell. 2004 Apr;5(4):341-51. doi: 10.1016/s1535-6108(04)00080-7.

Abstract

Thymidylate synthase (TS) is an E2F1-regulated enzyme that is essential for DNA synthesis and repair. TS protein and mRNA levels are elevated in many human cancers, and high TS levels have been correlated with poor prognosis in patients with colorectal, breast, cervical, bladder, kidney, and non-small cell lung cancers. In this study, we show that ectopic expression of catalytically active TS is sufficient to induce a transformed phenotype in mammalian cells as manifested by foci formation, anchorage independent growth, and tumor formation in nude mice. In contrast, comparable levels of two TS mutants carrying single point mutations within the catalytic domain had no transforming activity. In addition, we show that overexpression of TS results in apoptotic cell death following serum removal. These data demonstrate that TS exhibits oncogene-like activity and suggest a link between TS-regulated DNA synthesis and the induction of a neoplastic phenotype.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis
  • Cell Adhesion / drug effects
  • Cell Transformation, Neoplastic
  • Colony-Forming Units Assay
  • DNA Replication
  • DNA, Neoplasm / biosynthesis*
  • Doxorubicin / pharmacology
  • Gene Expression Regulation, Enzymologic / physiology
  • Humans
  • Kidney / drug effects
  • Kidney / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • NIH 3T3 Cells
  • Neoplasms, Experimental / enzymology*
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Oncogenes / physiology*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • RNA, Small Interfering / pharmacology
  • Thymidylate Synthase / physiology*

Substances

  • Antibiotics, Antineoplastic
  • DNA, Neoplasm
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • Doxorubicin
  • Thymidylate Synthase