Control of DNA polymerase-α activity in regenerating rat liver by calcium and 1α,25(OH)2D3

Authors

  • R. H. Rixon,

    Corresponding author
    1. Cellular Oncology Group, Division of Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, K1A OR6
    • Cellular Oncology Group, Division of Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, K1A OR6
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  • R. J. Isaacs,

    1. Cellular Oncology Group, Division of Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, K1A OR6
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  • J. F. Whitfield

    1. Cellular Oncology Group, Division of Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada, K1A OR6
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Abstract

The late G1 surge of DNA polymerase-α activity and the initiation of DNA replication in the hepatocytes of partial hepatectomy-induced regenerating liver were severely reduced when the mitogenic partial hepatectomy was carried out in the hypocalcemic and 1,25(OH)2D3 (1α,25-dihydroxycholecalciferol)-deficient environment of parathyroidectomized (PTX) or thyroparathyroidectomized (TPTX) rats. These inhibitions were prevented in TPTX rats by a postpartial hepatectomy injection of 1,25(OH)2D3, which also restored blood calcium to normocalcemic levels. Inhibition of active DNA polymerase-α accumulation and initiation of DNA synthesis in TPTX rats were also completely prevented by prefeeding the rats a low phosphorus diet, which stopped the lowering of the blood levels of calcium and 1,25(OH)2D3 following parathyroid removal. These studies indicate that the rise of DNA polymerase-α activity and the initiation of DNA replication in regenerating liver are controlled by cellular processes that rely on normal blood levels of calcium and 1,25(OH)2D3. Because DNA polymerase-α is the third DNA replication enzyme (the others are ribonucleotide reductase and thymidylate synthase) that has been shown to depend on parathyroid hormone and/or the circulating levels of calcium and 1,25(OH)2D3 that it controls, the authors concluded that the processes dependent on calcium and 1,25(OH)2D3 are parts of a mechanism that coordinately activates the DNA-replicating enzymes. The possibility that cyclic adenosine monophosphate (cAMP)-dependent protein kinases are involved in this replication mechanism is considered.

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