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Transgenic expression of human thymidylate synthase accelerates the development of hyperplasia and tumors in the endocrine pancreas

Oncogene volume 26, pages 4817–4824 (2007)Cite this article

Abstract

Thymidylate synthase (TS) is an essential enzyme for DNA synthesis and repair and elevated levels of TS have been identified as an important prognostic biomarker for colorectal cancer and several other common human malignancies. In addition, TS gene expression has been linked with cell-cycle regulation and cell proliferation through the ability of retinoblastoma protein to repress the transcriptional activation of E2F target genes such as TS. Therefore, overproduction of TS could participate in the progression to a neoplastic phenotype. Consistent with this model, a recent study has suggested that ectopic TS expression can induce a transformed phenotype in mammalian cells. To investigate the role of deregulated TS activity in tumor development, we generated transgenic mice that express high levels of catalytically active human TS (hTS) exclusively in the pancreas and low levels of hTS in multiple other tissues. Analyses of pancreatic tissue in TS transgenic mice revealed abnormalities within the endocrine pancreas, ranging from pancreatic islet hyperplasia to the detection of islet cell tumors. Overexpression of hTS in murine islets provides a new model to study genetic alterations associated with the progression from normal cells to hyperplasia to islet cell tumors, and suggests that this mouse model may be useful for regulating TS activity in vivo for development of cancer prevention and new therapies.

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Acknowledgements

We thank Alfredo Martinez for help with islet cells isolation, Steve Jay for help with the animals and Philip Martin for helpful discussions. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research and has complied with all relevant federal guidelines and NIH policies.

Author information

Author notes

  1. L Rahman

    Present address: 6Current address: Center for Scientific Review, NIH, Bethesda, MD 20892, USA.,

  2. E Kastanos

    Present address: 7Current address: Department of ECE, University of Cyprus, Nicosia 1678, Cyprus.,

  3. C Allegra

    Present address: 8Current address: Network for Medical Communication and Research, Bethesda, MD, USA.,

  4. M Chen and L Rahman: These two authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Therapeutics Program, Center for Cancer Research, Bethesda, MD, USA

    M Chen, L Rahman, D Voeller, E Kastanos, C Allegra, P Steeg & M Zajac-Kaye

  2. Division of Cancer Treatment and Diagnosis, National Clinical Target Validation Laboratory, Bethesda, MD, USA

    S X Yang

  3. Laboratory of Animal Sciences, NCI-Frederic Cancer Research, Frederick, MD, USA

    L Feigenbaum

  4. Genetic Branch, National Cancer Institute, Bethesda, MD, USA

    F J Kaye

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  1. M Chen
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Correspondence to M Zajac-Kaye.

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Chen, M., Rahman, L., Voeller, D. et al. Transgenic expression of human thymidylate synthase accelerates the development of hyperplasia and tumors in the endocrine pancreas. Oncogene 26, 4817–4824 (2007). https://doi.org/10.1038/sj.onc.1210273

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