Cell cycle-mediated regulation of hepatic regeneration

doi:10.1016/S0039-6060(97)90334-2

Surgery

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

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

NLR Bucher
Regeneration of mammalian liver
Int Rev Cytol
(1963)
P Nurse
Ordering S phase and M phase in the cell cycle
Cell
(1994)
CJ Sherr
G₁ phase progression: cycling on cue
Cell
(1994)
CJ Sherr
D-type cyclins
Trends Biochem Sci
(1995)
JH Albrecht et al.
Distinct patterns of cyclin D1 regulation in models of liver regeneration and human liver
Biochem Biophys Res Commun
(1995)
P Loyer et al.
Expression and activation of cdks (1 and 2) and cyclins in the cell cycle progression during liver regeneration
J Biol Chem
(1994)
XP Lu et al.
Induction of cyclin mRNA and cyclin-associated histone H1 kinase during liver regeneration
J Biol Chem
(1992)
W Kruijer et al.
Proto-oncogene expression in regenerating liver is stimulated in cultures of primary adult rat hepatocytes
J Biol Chem
(1986)
JW Grisham
A morphologic study of deoxyribonucleic acid synthesis and cell proliferation in regenerating liver: autoradiography with thymidine-H3
Cancer Res
(1962)
GK Michalopoulos
Liver regeneration: molecular mechanisms of growth control
FASEB J
(1990)

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)

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In the last few years, several studies have revisited long-held paradigm and postulated the fundamentally new vision on the mechanisms of cell-cycle regulation during liver regeneration.
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It appears that the cytokines TNF-α and IL-6 are early initiators of DNA synthesis in regenerating hepatocytes, although it is not clear whether their roles are facultative or triggering [110, 111]. Cell cycle progression requires, in addition to these hepatotrophic factors, activation of cyclin-dependent kinases (Cdks) that are regulated by cyclins and Cdks inhibitors [112]. The Cdks inhibitor p21 has been identified as an important protein in halting liver regeneration and may be induced by the presence of the hepatocyte proliferative inhibitor transforming growth factor-β (TGF-β[113, 114].
While major liver resections have become increasingly safe due to better understanding of anatomy and refinement of operative techniques, liver failure following partial hepatectomy still occurs from time to time and remains incompletely understood. Observationally, certain high-risk circumstances exist, namely, massive resection with small liver remnants, preexisting liver disease, and advancing age, where liver failure is more likely to happen. Upon review of available clinical and experimental studies, an interplay of factors such as impaired regeneration, oxidative stress, preferential triggering of apoptotic pathways, decreased oxygen availability, heightened energy-dependent metabolic demands, and energy-consuming inflammatory stimuli work to produce failing hepatocellular functions.
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One of the reasons for utilizing multiple cyclin D1 antibodies was that we were encountering difficulties in detecting cyclin D1-associated CDK activity in liver homogenates. The methodology we employed is similar to that in several reports of cell cycle regulation during liver regeneration [18,25–27]. While this methodology has been reported to be effective for the detection of cyclin D-associated CDK activity, in our hands the assay did not reproducibly detect cyclin D-associated kinase activity above levels seen in control immunoprecipitations.
Initiation and progression through G1 requires the activity of signaling complexes containing cyclins (D- or E-type) and cyclin-dependent kinases (CDK4/6 and CDK2, respectively). We set out to identify the G1-phase cyclins and CDKs that are operative during late gestation liver development in the rat. This is a period during which hepatocytes show a high rate of proliferation that is, at least in part, independent of the mitogenic signaling pathways that are functional in mature hepatocytes. RNase protection assay and Western immunoblotting indicated that cyclin D1 is expressed at similar levels in fetal and adult liver. When cyclin D1 was induced after partial hepatectomy, its predominant CDK-binding partner was CDK4. In contrast, cyclins D2 and D3 predominated in fetal liver and were complexed with both CDK4 and CDK6. Little CDK6 protein was expressed in quiescent or regenerating adult liver. Cyclins E1 and E2 were both transcriptionally up-regulated in fetal liver. Activity of complexes containing cyclins E1 and E2 was higher in fetal liver, as was content of the cell cycle regulator, Rb. In fetal liver, Rb was highly phosphorylated at both cyclin D- and cyclin E-dependent sites. In conclusion, liver development is associated with a switch from cyclin D2/D3-containing complexes to cyclin D1:CDK4 complexes. We speculate that the switch in D-type cyclins may be associated with the dependence on mitogenic signaling that develops as hepatocytes mature.
Regulation of Hepatocyte Cell Cycle Progression and Differentiation by Type I Collagen Structure
2005, Current Topics in Developmental Biology
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Among the cell cycle regulatory gene products expressed in response to growth factor stimulation are the cyclins, cell cycle regulatory proteins that associate with cyclin‐dependent kinases (cdks) to form active kinase complexes that regulate progression through cell cycle checkpoints. The G1‐ and S‐phase–specific cyclins, cyclin D1, cyclin E, and cyclin A, are expressed during both liver regeneration and hepatocyte proliferation in vitro (Albrecht et al., 1993; Ehrenfried et al., 1997). Overexpression of cyclin D1 in cultured hepatocytes or in intact liver in vivo can drive entry into the S phase independent of growth factors (Albrecht and Hansen, 1999; Nelsen et al., 2001).
Cell behavior is strongly influenced by the extracellular matrix (ECM) to which cells adhere. Both chemical determinants within ECM molecules and mechanical properties of the ECM network regulate cellular response, including proliferation, differentiation, and apoptosis. Type I collagen is the most abundant ECM protein in the body with a complex structure that can be altered in vivo by proteolysis, cross‐linking, and other processes. Because of collagen's complex and dynamic nature, it is important to define the changes in cell response to different collagen structures and its underlying mechanisms. This chapter reviews current knowledge of potential mechanisms by which type I collagen affects cell behavior, and it presents data that elucidate specific intracellular signaling pathways by which changes in type I collagen structure differentially regulate hepatocyte cell cycle progression and differentiation. A network of polymerized fibrillar type I collagen (collagen gel) induces a highly differentiated but growth‐arrested phenotype in primary hepatocytes, whereas a film of monomeric collagen adsorbed to a rigid dish promotes cell cycle progression and dedifferentiation. Studies presented here demonstrate that protein kinase A (PKA) activity is significantly elevated in hepatocytes on type I collagen gel relative to collagen film, and inhibition of this elevated PKA activity can promote hepatocyte cell cycle progression on collagen gel. Additional studies are presented that examine changes in hepatocyte cell cycle progression and differentiation in response to increased rigidity of polymerized collagen gel by fiber cross‐linking. Potential mechanisms underlying these cellular responses and their implications are discussed.
Effects of SIRPα1 on liver regeneration after partial hepatectomy in rat
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SIRPα1 is well known as a negative regulator for cell proliferation through the regulation of the activity of receptor tyrosine kinase with ITAM motif. No investigation to data was undertaken on SIRPα1 involving liver regeneration.
Adult male Sprague—Dawley rats underwent approximately 70% partial hepatectomy (PH) or sham operation (SO). Liver specimens were collected at 2, 6, 12, 24, 30, 48, 72, 120, 168, and 240h after PH or SO. SIRPα1 expression was determined in mRNA level by Northern blotting as well as in protein levels via immunohistochemical staining.
SO treatment did not induce remarkable changes in SIRPα1 expression; however, the level of a 3.9-kb transcript for SIRPα1 was significantly up-regulated after PH (versus SO, P < 0.05). SIRPα1 mRNA expression in the regenerating liver displayed a biphasic response with its first large peak at as early as 12h followed by a second phase of up-regulation from 48 to 120h post-PH. SIRPα1 mRNA expression returned to its physiological level 168h later. As seen from immunohistochemistry experiments, SIRPα1 protein mainly located in membrane was expressed uniquely in regenerating hepatocytes. Similarly, PH-induced overexpression for SIRPα1 protein occurred between 12 and 168h with a peak level at 24h after surgery.
SIRPα1, a principle negative regulator for cell proliferation, may also play a role in the termination of hepatic proliferation during liver regeneration induced by physiological stress or pathological states, such as PH, drugs, toxins, etc.
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^☆: 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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Original communicationCell cycle-mediated regulation of hepatic regeneration☆

Abstract

Int Rev Cytol

Cell

Cell

Trends Biochem Sci

Biochem Biophys Res Commun

J Biol Chem

J Biol Chem

J Biol Chem

A morphologic study of deoxyribonucleic acid synthesis and cell proliferation in regenerating liver: autoradiography with thymidine-H3

Cancer Res

Liver regeneration: molecular mechanisms of growth control

FASEB J

Analysis of cell cycle compartments of hepatocytes after partial hepatectomy

Cell Tissue Kinet

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

Irreversible injury

Pharmacol Rev

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

Arch Pathol

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

Am J Physiol

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

Hepatology

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

FASEB J

Cyclins in the cell cycle: an overview

Microbiol Immunol

Principles of CDK regulation

Nature

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

Bioessays

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

Science

Original communication
Cell cycle-mediated regulation of hepatic regeneration☆

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