Regulation of Cyclin D-Dependent Kinase Activity in Rat Liver Regeneration

Kato, Akira; Ota, Shinichi; Bamba, Hiromi; Wong, Rei Ming; Ohmura, Eiji; Imai, Yasuo; Matsuzaki, Fumio

doi:10.1006/bbrc.1998.8377

Cited by 25 publications

(25 citation statements)

References 19 publications

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“…Our results are in agreement with both articles in the sense that quiescent cells contain very low amounts of cyclin D1-cdk4 complexes and that these complexes are formed during G 1 . 31,32 Results reported here indicate that in quiescent cells, cyclin D1 is mostly nuclear, whereas cdk4 and cyclin D3 are cytoplasmic; thus, one can argue that cyclin D1 could not form complexes with cdk4 in quiescent cells, because they are located in different intracellular compartments. Likewise, the presence of cyclin D3 and cdk4 in the cytoplasm of quiescent cells could explain the existence of cyclin D3-cdk4 complexes in these cells.…”

Section: Discussionmentioning

confidence: 72%

Activation of Cdk4 and Cdk2 During Rat Liver Regeneration Is Associated With Intranuclear Rearrangements of Cyclin–Cdk Complexes

et al. 1999

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Partial hepatectomy (PH) triggers the entry of rat liver cells into the cell cycle. The signals leading to cell-cycle activation converge into a family of kinases named cyclindependent kinases (cdks). Specific cyclin-cdk complexes are sequentially activated during the cell cycle. Cyclin D-cdk4 and cyclin E-cdk2 are activated during the G 1 phase, cyclin A-cdk2 is activated during the S phase, and cyclin B-cdk1 during mitosis. In the present study, we have examined the timing of the activation of cdk4 and cdk2, the intracellular location of G 1 /S cyclins and cdks, and the relationship between location and cdk4 and cdk2 activities during rat liver regeneration after a PH. Results showed that the activity of both kinases started at 13 hours and showed maximal levels at 24 hours after hepatectomy. In quiescent cells, cyclin D3 and cdk4 were cytoplasmatic, whereas cyclin D1 was nuclear. At 5 hours after hepatectomy, cyclin D3 and cdk4 began to move into the nucleus, and at 13 hours, they were mostly nuclear. During the first 13 hours after hepatectomy, significant amounts of cyclin D1-cdk4 and cyclin D3-cdk4 complexes were formed, but they were mostly inactive. At 24 hours, these complexes were maximally activated. This activation was associated with the accumulation of cyclin D1, cyclin D3, and cdk4 in a nuclear subfraction extractable with nucleases. At 28 hours, the activity of cdk4 in this nuclear subfraction decreased when cyclin D1 moved from this fraction to the nuclear matrix (NM) and the levels of cyclin D3 diminished. The maximal activation of cdk2 at 24 hours was also associated with the accumulation of cyclin E, cyclin A, and cdk2 in this nuclease-sensitive fraction. The inactivation of cdk2 at 28 hours was associated with a strong decrease in cdk2 in this nuclear subfraction. Thus, results reported here indicate that the activation of cdk4 and cdk2 observed in rat liver cells after a PH is associated with a specific intranuclear location of these cdks and their associated cyclins. (HEPATOL-OGY 1999;29:385-395.)In pluricellular organisms, the cell cycle is regulated by growth factors, anchorage to the extracellular matrix, and contact inhibition. These extracellular factors generate intracellular signals that finally converge into a family of serinethreonine kinases, named cyclin-dependent kinases (cdks), which act as molecular integrators of the signals that regulate cell-cycle progression.The liver contains hepatocytes (85%-95% of the hepatic mass) and nonhepatocytes (5%-15% of hepatic mass). In normal livers from adult animals, all these cells are quiescent.

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Section: Discussionmentioning

confidence: 72%

Activation of Cdk4 and Cdk2 During Rat Liver Regeneration Is Associated With Intranuclear Rearrangements of Cyclin–Cdk Complexes

et al. 1999

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“…The expression of p21, but not p27, has been related to hepatocellular proliferation in experimental liver resection. 43,44 Nevertheless, p27 mRNA and protein expression is enhanced in EGFstimulated hepatocytes. 45 Genotoxic stress induced by DNA damaging chemicals causes a variety of cellular and molecular responses in mammalian cells, including cell cycle arrest, DNA repair and apoptosis.…”

Section: Discussionmentioning

confidence: 98%

The reduction of cell death and proliferation by p27^Kip1 minimizes DNA damage in an experimental model of genotoxicity

Ranchal

González

Bello

et al. 2009

Intl Journal of Cancer

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Hepatocellular carcinoma (HCC) is the fifth most commonly occurring cancer worldwide. The expression of p27 has been related to reduced severity of tumor grade and recurrence of HCC. The study assessed the role of p27 on the cell proliferation and death, and DNA mutagenesis in experimental genotoxicity induced by aflatoxin B1 (AFB 1 ) in cultured hepatocytes obtained from control and p27Kip1 deficient mice. The overexpression of p27 was assessed with wild type p27Kip1 expression vector in HepG2 cells. The expression of p27, p21 and p53 was assessed in well and poorly-differentiated liver tumors. DNA damage and cell death induced by AFB 1 were related to a reduction of p27 and p21 expression in cultured hepatocytes. AFB 1 -induced nuclear phosphorylated (Ser 10) p27 degradation was related to a rise of nuclear KIST, Rsk-1 and Rsk-2 expression and cytoplasm phosphorylated (Thr 198) p27 expression. The overexpression of p27 reduced cell proliferation, cell death and DNA damage in AFB 1 -treated hepatocytes. The enhanced survival of patients with well differentiated compared to poorly-differentiated tumors was related to high expression of p27, p21 and p53 in liver sections. The study showed that the p27 reduced cell proliferation and death, as well as the accumulation of DNA damage in hepatocarcinogenesis. ' 2009 UICC

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“…The liver compensates for necrosis with cell division, and expression of PCNA and G 1 /S cyclin (cyclin D1 and Cdk4) was detected within 48 h after LPS injury. Cyclin D1 mediates progression from the quiescent gap 0 (G 0 ) phase of the cycle through G 1 (40), and cyclin D1 and Cdk presence in the nucleus after LPS indicates binding associated with mitosis-regulating retinoblastoma kinase activity (41). Regulation of cyclin D1/Cdk4 complex formation and translocation varies among cells (41), but in late G 1 and during S phase PCNA (cyclin A) binds DNA polymerase-␦ (42,43), and its expression is sensitive to proliferation (44) and consistent with liver regeneration (45).…”

Section: Discussionmentioning

confidence: 99%

Lipopolysaccharide Stimulates Mitochondrial Biogenesis via Activation of Nuclear Respiratory Factor-1

Suliman

Carraway

Welty-Wolf

et al. 2003

Journal of Biological Chemistry

165

122

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Exposure to bacterial lipopolysaccharide (LPS) in vivo damages mitochondrial DNA (mtDNA) and interferes with mitochondrial transcription and oxidative phosphorylation (OXPHOS). Because this damage accompanies oxidative stress and is reversible, we postulated that LPS stimulates mtDNA replication and mitochondrial biogenesis via expression of factors responsive to reactive oxygen species, i.e. nuclear respiratory factor-1 (NRF-1) and mitochondrial transcription factor-A. In testing this hypothesis in rat liver, we found that LPS induces NRF-1 protein expression and activity accompanied by mRNA expression for mitochondrial transcription factor-A, mtDNA polymerase ␥, NRF-2, and single-stranded DNA-binding protein. These events restored the loss in mtDNA copy number and OXPHOS gene expression caused by LPS and increased hepatocyte mitotic index, nuclear cyclin D1 translocation, and phosphorylation of pro-survival kinase, Akt. Thus, NRF-1 was implicated in oxidant-mediated mitochondrial biogenesis to provide OXPHOS for proliferation. This implication was tested in novel mtDNA-deficient cells generated from rat hepatoma cells that overexpress NRF-1. Depletion of mtDNA ( o clones) diminished oxidant production and caused loss of NRF-1 expression and growth delay. NRF-1 expression and growth were restored by exogenous oxidant exposure indicating that oxidative stress stimulates biogenesis in part via NRF-1 activation and corresponding to recovery events after LPS-induced liver damage.

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Regulation of Cyclin D-Dependent Kinase Activity in Rat Liver Regeneration

Cited by 25 publications

References 19 publications

Activation of Cdk4 and Cdk2 During Rat Liver Regeneration Is Associated With Intranuclear Rearrangements of Cyclin–Cdk Complexes

Activation of Cdk4 and Cdk2 During Rat Liver Regeneration Is Associated With Intranuclear Rearrangements of Cyclin–Cdk Complexes

The reduction of cell death and proliferation by p27^Kip1 minimizes DNA damage in an experimental model of genotoxicity

Lipopolysaccharide Stimulates Mitochondrial Biogenesis via Activation of Nuclear Respiratory Factor-1

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Regulation of Cyclin D-Dependent Kinase Activity in Rat Liver Regeneration

Cited by 25 publications

References 19 publications

Activation of Cdk4 and Cdk2 During Rat Liver Regeneration Is Associated With Intranuclear Rearrangements of Cyclin–Cdk Complexes

Activation of Cdk4 and Cdk2 During Rat Liver Regeneration Is Associated With Intranuclear Rearrangements of Cyclin–Cdk Complexes

The reduction of cell death and proliferation by p27Kip1 minimizes DNA damage in an experimental model of genotoxicity

Lipopolysaccharide Stimulates Mitochondrial Biogenesis via Activation of Nuclear Respiratory Factor-1

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The reduction of cell death and proliferation by p27^Kip1 minimizes DNA damage in an experimental model of genotoxicity