title: Calorie restriction influences cell cycle protein expression and DNA synthesis during liver regeneration.
abstract: Calorie restriction without essential nutrient deficiency (calorie restriction, CR) abrogates experimental carcinogenesis and extends healthful life span. To test whether CR influences cell-cycle protein expression during the hepatocellular proliferation induced by 70% partial hepatectomy (PH), BALB/c mice were separated into two groups, fed comparable semi-purified diets for 10 weeks that differed 40% in caloric offering, and were then subjected to PH. When PH was performed, CR mice weighed 36% less than ad libitum (AL)-fed mice (P < 0.01), but liver-to-body weight ratios were similar. During the regenerative hyperplasia, hepatocytes of CR mice demonstrated evidence of accelerated entrance and passage through G1 and S phases, and an earlier exit from the cell cycle. The first peak of DNA synthesis occurred 6 hr earlier, and the second peak was significantly greater among CR mice with 38% +/- 13% bromodeoxyuridine (BrdU)-positive hepatocytes, compared with 14% +/- 4% in AL mice (P < 0.01). More E2F-1 expression was induced at the hepatic G1/S boundary just prior to each peak of DNA synthesis in regenerating livers of CR mice (P < 0.01), and 8 hr earlier among CR mice. More hyperphosphorylated retinoblastoma p110 was detected during hepatic G1 and the G1-S transition among CR mice, coincident with the early hepatocellular proliferative wave. Cyclin A was induced during the first peak of DNA synthesis 4 hr earlier among CR mice, and it continued 4 hr longer in AL mice, indicating an earlier post-replicative exit by hepatocytes in CR mice. p21 was induced during the G1 phase at 4 hr post-PH, and was maximally expressed during and after peak DNA synthesis in both dietary groups. These results indicate that CR influences cell cycle protein expression levels, causing hepatocytes to enter into S phase earlier and exit abruptly from the cell cycle, and they support the premise that CR enhances induced cell responsiveness by influencing cell cycle regulatory controls.
authors.affiliation: Department of Pediatrics, College of Medicine, University of South Florida, Tampa, Florida 33612, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Cuenca
authors.forename: W D
authors.initials: WD
authors.lastname: Cress
authors.forename: R A
authors.initials: RA
authors.lastname: Good
authors.forename: Y
authors.initials: Y
authors.lastname: Marikar
authors.forename: R W
authors.initials: RW
authors.lastname: Engelman
mesh_terms: D000367:Age Factors; D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D002453:Cell Cycle; D002455:Cell Division; D004247:DNA / Q000096:biosynthesis; D002149:Energy Intake; D005260:Female; D006498:Hepatectomy; D008099:Liver / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D012038:Regeneration; D016196:S Phase; D013997:Time Factors
chemical_list: D004247:DNA