Thymidine kinase 1 through the ages: a comprehensive review
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Cell & Bioscience Open Access
REVIEW
Thymidine kinase 1 through the ages: a comprehensive review Eliza E. Bitter*, Michelle H. Townsend, Rachel Erickson, Carolyn Allen and Kim L. O’Neill*
Abstract Proliferation markers, such as proliferating cell nuclear antigen (PCNA), Ki-67, and thymidine kinase 1 (TK1), have potential as diagnostic tools and as prognostic factors in assessing cancer treatment and disease progression. TK1 is involved in cellular proliferation through the recovery of the nucleotide thymidine in the DNA salvage pathway. TK1 upregulation has been found to be an early event in cancer development. In addition, serum levels of TK1 have been shown to be tied to cancer stage, so that higher levels of TK1 indicate a more serious prognosis. As a result of these findings and others, TK1 is not only a potentially viable biomarker for cancer recurrence, treatment monitoring, and survival, but is potentially more advantageous than current biomarkers. Compared to other proliferation markers, TK1 levels during S phase more accurately determine the rate of DNA synthesis in actively dividing tumors. Several reviews of TK1 elaborate on various assays that have been developed to measure levels in the serum of cancer patients in clinical settings. In this review, we include a brief history of important TK1 discoveries and findings, a comprehensive overview of TK1 regulation at DNA to protein levels, and recent findings that indicate TK1’s potential role in cancer pathogenesis and its growing potential as a tumor biomarker and therapeutic target. Keywords: Thymidine kinase 1, TK1, Biomarker, Regulation, Tumorigenesis, Assay Background Thymidine kinase 1 (TK1) is a DNA salvage pathway enzyme involved in regenerating thymidine for DNA synthesis and DNA damage. Thymidine is transferred from the extracellular space across the cell membrane by facilitated diffusion and is converted to its monophosphate form (dTMP) within the cytosol by TK1 [1, 2]. Successive enzymes within the cytosol then convert dTMP to its triphosphate form deoxythymidine triphosphate (dTTP) prior to DNA replication. Nucleotides such as dTTP are passively imported into the nucleus through a nuclear pore complex for DNA synthesis and transcription [3]. The de novo pathway is an alternative for regenerating nucleotides but it is anabolic in nature and therefore less favorable when conserving cell energy. During de novo
*Correspondence: [email protected]; [email protected] Department of Microbiology and Molecular Biology, Brigham Young University, 701 E University Pkwy, LSB room 4007, Provo, UT 84602, USA
synthesis, deoxyuridine monophosphate (dUMP) is converted to dTMP by thymidylate synthase in the presence of folic acid and vitamin B12 [4]. Because the salvage pathway is less energetically expensive, it is usually the preferred generation pathway within the cell [5]. With the availability of two pathways for dTTP generation, TK1 is not essential for cell viability [6]. Aside from DNA synthesis, TK1 is essential to cell repair following DNA d
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