Control of DNA polymerase-alpha activity in regenerating rat liver by calcium and 1 alpha,25(OH)2D3.
The late G1 surge of DNA polymerase-alpha 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 (1 alpha,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-alpha 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-alpha 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-alpha 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.
Rixon
R H
RH
Division of Biological Sciences, National Research Council of Canada, Ottawa, Ontario.
Isaacs
R J
RJ
Whitfield
J F
JF
D000818:Animals; D002117:Calcitriol / Q000502:physiology*; D002118:Calcium / Q000502:physiology*; D004247:DNA / Q000096:biosynthesis; D004257:DNA Polymerase II / Q000378:metabolism*; D006498:Hepatectomy; D008099:Liver / Q000201:enzymology; D008115:Liver Regeneration; D008297:Male; D010280:Parathyroid Glands / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D013965:Thyroidectomy
D004247:DNA; D004257:DNA Polymerase II; D002117:Calcitriol; D002118:Calcium