Regenerating livers of old rats contain high levels of C/EBPα that correlate with altered expression of cell cycle associated proteins

Nikolai A. Timchenko, Margaret Wilde, Ken Lchiro Kosai, Ahmed Heydari, Timothy A. Bilyeu, Milton J. Finegold, Khalid Mohamedali, Arlan Richardson, Gretchen J. Darlington

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Abstract

The nuclear transcription factor, CCAAT/enhancer binding protein α (C/EBPα) is expressed at high levels in the liver and inhibits growth in cultured cells. We have tested the correlation between C/EBPα levels, cell cycle proteins and hepatocyte proliferation in old and young animals as an in vivo model system in which the proliferative response to partial hepatectomy (PH) has been shown to be reduced and delayed in old animals. Here we present evidence that the expression of C/EBPα in old rats (24 months) differs from its expression in young animals (6-10 months) during liver regeneration. Induction of proliferating cell nuclear antigen (PCNA), a marker of DNA synthesis, occurs at 24 h after PH in young rats but is delayed and reduced in old animals. Induction of the mitotic-specific protein, cdc2 p34, is 3-4-fold less in regenerating liver of old rats than in the liver of young animals, confirming the reduced proliferative response in old animals. In young rats, the normal regenerative response involves a reduction of 3-4-fold in the levels of C/EBPα protein at 3-24 h. In old animals, C/EBPα is not reduced within 24 h after PH, but a decrease of C/EBPα protein levels can be detected at 72 h after PH. Induction of C/EBPβ, another member of the C/EBP family, is delayed in old animals. Changes in the expression of C/EBP proteins are accompanied by alteration of the CDK inhibitor, p21, which is also decreased in young rats after PH, but in old animals remains unchanged. High levels of p21 protein in older animals correlate with the lack of cdk2 activation. We suggest that the failure to reduce the amount of C/EBPα and p21 is a critical event in the dysregulation of hepatocyte proliferation in old animals following PH.

Original languageEnglish (US)
Pages (from-to)3293-3299
Number of pages7
JournalNucleic Acids Research
Volume26
Issue number13
DOIs
StatePublished - Jul 1 1998
Externally publishedYes

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CCAAT-Enhancer-Binding Proteins
Cell Cycle Proteins
Hepatectomy
Liver
Hepatocytes
Proteins
CDC2 Protein Kinase
Liver Regeneration
Proliferating Cell Nuclear Antigen
Genetic Markers
Cultured Cells
Transcription Factors

ASJC Scopus subject areas

  • Genetics

Cite this

Timchenko, N. A., Wilde, M., Kosai, K. L., Heydari, A., Bilyeu, T. A., Finegold, M. J., ... Darlington, G. J. (1998). Regenerating livers of old rats contain high levels of C/EBPα that correlate with altered expression of cell cycle associated proteins. Nucleic Acids Research, 26(13), 3293-3299. https://doi.org/10.1093/nar/26.13.3293

Regenerating livers of old rats contain high levels of C/EBPα that correlate with altered expression of cell cycle associated proteins. / Timchenko, Nikolai A.; Wilde, Margaret; Kosai, Ken Lchiro; Heydari, Ahmed; Bilyeu, Timothy A.; Finegold, Milton J.; Mohamedali, Khalid; Richardson, Arlan; Darlington, Gretchen J.

In: Nucleic Acids Research, Vol. 26, No. 13, 01.07.1998, p. 3293-3299.

Research output: Contribution to journalArticle

Timchenko, NA, Wilde, M, Kosai, KL, Heydari, A, Bilyeu, TA, Finegold, MJ, Mohamedali, K, Richardson, A & Darlington, GJ 1998, 'Regenerating livers of old rats contain high levels of C/EBPα that correlate with altered expression of cell cycle associated proteins', Nucleic Acids Research, vol. 26, no. 13, pp. 3293-3299. https://doi.org/10.1093/nar/26.13.3293
Timchenko, Nikolai A. ; Wilde, Margaret ; Kosai, Ken Lchiro ; Heydari, Ahmed ; Bilyeu, Timothy A. ; Finegold, Milton J. ; Mohamedali, Khalid ; Richardson, Arlan ; Darlington, Gretchen J. / Regenerating livers of old rats contain high levels of C/EBPα that correlate with altered expression of cell cycle associated proteins. In: Nucleic Acids Research. 1998 ; Vol. 26, No. 13. pp. 3293-3299.
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abstract = "The nuclear transcription factor, CCAAT/enhancer binding protein α (C/EBPα) is expressed at high levels in the liver and inhibits growth in cultured cells. We have tested the correlation between C/EBPα levels, cell cycle proteins and hepatocyte proliferation in old and young animals as an in vivo model system in which the proliferative response to partial hepatectomy (PH) has been shown to be reduced and delayed in old animals. Here we present evidence that the expression of C/EBPα in old rats (24 months) differs from its expression in young animals (6-10 months) during liver regeneration. Induction of proliferating cell nuclear antigen (PCNA), a marker of DNA synthesis, occurs at 24 h after PH in young rats but is delayed and reduced in old animals. Induction of the mitotic-specific protein, cdc2 p34, is 3-4-fold less in regenerating liver of old rats than in the liver of young animals, confirming the reduced proliferative response in old animals. In young rats, the normal regenerative response involves a reduction of 3-4-fold in the levels of C/EBPα protein at 3-24 h. In old animals, C/EBPα is not reduced within 24 h after PH, but a decrease of C/EBPα protein levels can be detected at 72 h after PH. Induction of C/EBPβ, another member of the C/EBP family, is delayed in old animals. Changes in the expression of C/EBP proteins are accompanied by alteration of the CDK inhibitor, p21, which is also decreased in young rats after PH, but in old animals remains unchanged. High levels of p21 protein in older animals correlate with the lack of cdk2 activation. We suggest that the failure to reduce the amount of C/EBPα and p21 is a critical event in the dysregulation of hepatocyte proliferation in old animals following PH.",
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AU - Heydari, Ahmed

AU - Bilyeu, Timothy A.

AU - Finegold, Milton J.

AU - Mohamedali, Khalid

AU - Richardson, Arlan

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