Elsevier

Surgery

Volume 122, Issue 5, November 1997, Pages 927-935
Surgery

Original communication
Cell cycle-mediated regulation of hepatic regeneration

https://doi.org/10.1016/S0039-6060(97)90334-2Get rights and content

Abstract

Background. Hepatic regeneration after partial hepatectomy (PH) is characterized by a synchronous induction of normally quiescent hepatocytes to reenter the cell cycle, leading to a complete restoration of hepatic mass. Cell cycle progression requires activation of cyclin-dependent kinases (Cdks) that are regulated by cyclins and Cdk inhibitors.

Methods. Protein expression of the cyclins (D-type and E), Cdks (Cdk2 and 4), and Cdk inhibitors (p21 and p27) was measured by Western blot after SHAM operation or PH in F344 rats. In addition, Cdk2-associated kinase activity was measured.

Results. Rapid induction of D-type and E cyclins, as well as their catalytic partners, Cdk2 and Cdk4, occurred after PH in rats. Complexes containing cyclin E and Cdk2 assembled in the regenerating liver, leading to increased Cdk2-associated kinase activity. The regenerating liver returned to preresection weight by day 7, at which time the Cdk2 activity also returned to SHAM levels. Biphasic induction of the Cdk inhibitor p21 was observed; the first peak occurred as early as 6 hours after PH, with a subsequent peak in expression occurring at 24 to 72 hours after PH.

Conclusions. Taken together, these data support the concept that cyclins, Cdks, and Cdk inhibitors regulate cell cycle progression in the regenerating liver. In addition, the induction of p21 at two time points suggests that this protein may regulate both early proliferation and subsequent inhibition of hepatocyte regeneration.

References (43)

  • HM Rabes et al.

    Analysis of cell cycle compartments of hepatocytes after partial hepatectomy

    Cell Tissue Kinet

    (1976)
  • H Gerhard

    A quantitative model of cellular regeneration in rat liver after partial hepatectomy

  • EA Smuckler et al.

    Irreversible injury

    Pharmacol Rev

    (1984)
  • GM Higgins et al.

    Experimental pathology of the liver. I. Restoration of the liver of the white rat following partial surgical removal

    Arch Pathol

    (1931)
  • JH Albrecht et al.

    Cyclin and cyclin-dependent kinase 1 mRNA expression in models of regenerating liver and human liver diseases

    Am J Physiol

    (1993)
  • A Francavilla et al.

    Hormonal and enzymatic parameters of hepatic regeneration in patients undergoing major liver resections

    Hepatology

    (1990)
  • M Dorée et al.

    The cyclin-dependent protein kinases and the control of cell division

    FASEB J

    (1994)
  • J Hanley-Hyde

    Cyclins in the cell cycle: an overview

    Microbiol Immunol

    (1992)
  • DO Morgan

    Principles of CDK regulation

    Nature

    (1995)
  • EA Nigg

    Cyclin-dependent protein kinases: key regulators of the eukaryotic cell cycle

    Bioessays

    (1995)
  • V Dulic et al.

    Association of human cyclin E with a periodic G1-S phase protein kinase

    Science

    (1992)
  • Cited by (0)

    Supported by grant 8510 from the Shriners Burns Institute, grants PO1 DK 35608, R37 CA24347, and K08 CA64191 from the National Institutes of Health, and the James E. Thompson, M.D. Memorial Foundation.

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