Ras adenoviruses modulate cyclin E protein expression and DNA synthesis after partial hepatectomy

Lüdde, Tom; Kubicka, Stefan; Plümpe, Jörg; Liedtke, Christian; Manns, Michael P.

doi:10.1038/sj.onc.1204690

Cited by 24 publications

(39 citation statements)

References 51 publications

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“…Furthermore, a relationship between ras expression and cyclin E/Cdk2 seems to exist in regenerating hepatocytes. 13 In our experimental setting, determination of ras mRNA levels by quantitative PCR revealed a similar increase of the proto-oncogene in both the control and the treatment groups at 24 h after PH (Figure 7). Although the increase of ras mRNA was slightly lower at 16 h after PH in CYC202-treated animals compared to DMSOtreated rats, the difference between these groups did not reach the level of statistical significance.…”

Section: Cyc202 Does Not Interfere With Mid-g1 Events Of the Cell Cyclementioning

confidence: 96%

“…6,10 Cyclin E and Cdk2 induction, redistribution and activity have been shown to be disturbed in several models of impaired liver regeneration. [11][12][13] In addition, hepatocyte proliferation can be stimulated by targeted modulation of cyclin E. 14 Although, these data suggest that cyclin E and Cdk2 might be important in orchestrating the cell cycle in the regenerating liver, the exact role of the active cyclinE/Cdk2 complex remains to be defined.…”

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confidence: 99%

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Blunted DNA synthesis and delayed S-phase entry following inhibition of Cdk2 activity in the regenerating rat liver

Stärkel

Saeger

Sempoux

et al. 2005

Laboratory Investigation

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Activation of the cyclin E/Cdk2 complex may play an important role in mid-G1/S-phase progression in proliferating mammalian cells. We evaluated the effect of targeted inhibition of Cdk2 activity by CYC202 (Rroscovitine) on hepatocytes proliferation in vivo after 70% partial hepatectomy (PH) in rats. In controls, Cdk2 activity and DNA synthesis peaked 24 h after PH. CYC202 abrogated Cdk2 activity, prevented BrdU incorporation and PCNA expression and increased mortality 24 h after PH. Cyclin E and Cdk2 protein expression and complex formation was not affected by CYC202 nor was cyclin D1, Cdk4 and c-ras mRNA expression. Two consecutive injections 8 and 20 h after PH were required to elicit the inhibitory effect of CYC202, which was lost when either the injection at 8 h or at 20 h was withheld. Cdk2 activity and cell progression resumed 48 h after PH in surviving animals suggesting that CYC202 induced a reversible inhibition of the cell cycle. Our results confirm an important role for Cdk2 in hepatocytes proliferation in the regenerating liver. We demonstrate that molecular events, including Cdk2 activation, occurring within the 8th and 24th hour after PH (G1/S-phase transition) are crucial in determining whether or not DNA synthesis and hepatocytes proliferation proceed normally after PH.

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Section: Cyc202 Does Not Interfere With Mid-g1 Events Of the Cell Cyclementioning

confidence: 96%

mentioning

confidence: 99%

Blunted DNA synthesis and delayed S-phase entry following inhibition of Cdk2 activity in the regenerating rat liver

Stärkel

Saeger

Sempoux

et al. 2005

Laboratory Investigation

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“…Coimmunoprecipitation and histone H1 kinase assay were performed as previously described. 5 Cell Fixation and Staining. Cells were washed twice with phosphate-buffered saline (PBS) and fixed in 4% paraformaldehyde for 10 minutes at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Section: Uring Cell Division In Eukaryotic Cells Cyclin E1mentioning

confidence: 99%

“…After partial hepatectomy (PH) in mice, cyclin E1 expression increases and peaks at 36 hours after resection, which reflects the increasing number of dividing hepatocytes. 5,6 Therefore, cyclin E1 is used as a marker to monitor cell cycle progression during liver regeneration.Dysregulated cyclin E1 expression has been shown to act as a potent oncogene in some types of human cancer. Amplification of the cyclin E1 gene and cell cycle-independent overexpression promotes tumor development, particularly in breast cancer but also in hepatocellular carcinoma (HCC).…”

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Expression of a cyclin E1 isoform in mice is correlated with the quiescent cell cycle status of hepatocytesin vivo

et al. 2006

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Cyclin E1 controls G1/S phase transition of the eukaryotic cell cycle. We report the impact of alternative spliced cyclin E1 isoforms on cell cycle regulation in hepatocytes. We show that expression of new cyclin E1 mRNA variants IN3, ⌬4, and ⌬5 is associated with retarded proliferation in murine hepatocellular carcinoma. Additionally, we demonstrate that a new cyclin E1 isoform ⌬3/8 lacking the central part of wild-type mRNA is expressed predominantly in nonproliferating murine hepatocytes. Following partial hepatectomy, ⌬3/8 is downregulated when hepatocytes enter the cell cycle from quiescence. The ⌬3/8 protein does not exhibit any cyclin box motif but binds cyclin-dependent kinase 2 without stimulating kinase activity. We demonstrate that ⌬3/8 lacks any nuclear localization signal and is exclusively located in the cytoplasm. Overexpression of ⌬3/8 in cultured cells leads to a delayed G0-G1 transition, indicating that this splice variant helps to maintain a quiescent state of hepatocytes. In conclusion, we identified an isoform of cyclin E1 involved in G0 maintenance and suggest an additional mechanism for cell cycle control. ( D uring cell division in eukaryotic cells, cyclin E1 expression oscillates with a peak at G1/S phase transition. To coordinate progression of the cell cycle, cyclin E1 forms complexes with and controls kinase activity of cyclin-dependent kinase 2 (cdk2). 1-3 Thus, cyclin E1-cdk2 complexes phosphorylate substrates essential for a synchronized initiation of DNA replication, centrosome duplication, chromatin remodeling, and histone biogenesis at G1/S phase transition. 4 Moreover, in adult hepatocytes cyclin E1 plays an important role in cell cycle regulation. After partial hepatectomy (PH) in mice, cyclin E1 expression increases and peaks at 36 hours after resection, which reflects the increasing number of dividing hepatocytes. 5,6 Therefore, cyclin E1 is used as a marker to monitor cell cycle progression during liver regeneration.Dysregulated cyclin E1 expression has been shown to act as a potent oncogene in some types of human cancer. Amplification of the cyclin E1 gene and cell cycle-independent overexpression promotes tumor development, particularly in breast cancer but also in hepatocellular carcinoma (HCC). [7][8][9][10][11] Several reports have shown that overexpression of cyclin E1 accelerates G1 phase, decreases size of mitotic cells, promotes cell division independent from growth factors, and causes chromosomal instability in cancer cells. [12][13][14][15] Alternative splicing occurs in 60% of human genes 16 and modulates the oncogenic functions of BRCA1 and BRCA2 in breast cancer or Bcl2 in prostate cancer. 17,18 Several alternative spliced variants of human cyclin E1 have been isolated that modify cyclin function. [19][20][21] The biological functions of cyclin E1 alternative splice variants during cell cycle of normal or malignant cells are widely unknown.

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TNF ?-induced ras activation due to ethanol promotes hepatocyte proliferation independently of liver injury in the mouse

et al. 2004

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Tumor necrosis factor ␣ (TNF␣) has been shown to be both proapoptotic and mitogenic for hepatocytes and necessary for alcohol-induced liver injury. Ras, a known proto-oncogene, is very important in the regulation of cellular responses to TNF␣. Therefore, the purpose of this study was to investigate the role of Ras in alcohol-induced pathogenesis. Male C57Bl/6 mice were fed ethanol or high-fat control diet via intragastric cannulation for 4 weeks. Ras activity was increased significantly after 4 weeks of ethanol and correlated with an increase in pathologic features. However, in mice deficient in the receptor-type 1 for TNF␣ (TNFR1 -/-), ethanolinduced liver injury and the increase in Ras activity were significantly blunted compared with wild-type mice. Furthermore, it was demonstrated that H-, K-, and R-Ras isoforms were increased after ethanol exposure in wild-type mice. In TNFR1 -/-mice, R-Ras activity remained elevated by ethanol, whereas H-Ras and K-Ras activity was blunted significantly under these conditions. Interestingly, hepatocellular proliferation, which was elevated approximately fivefold after 4 weeks of chronic ethanol in wild-type mice, was also blunted in TNFR1 -/-mice given ethanol. Inhibition of Ras with adenovirus containing a dominant-negative Ras had no effect on ethanol-induced liver injury, but significantly blunted ethanol-induced hepatocyte proliferation by more than 50%. Overexpression of mitochondrial superoxide dismutase using recombinant adenovirus blunted lipid peroxidation and attenuated hepatic injury resulting from ethanol, but had no effect on Ras activation and hepatocyte proliferation caused by ethanol. In conclusion, these data support the hypotheses that hepatocellular oxidative stress leads to cell death and that TNF␣-induced Ras activation is important in hepatic proliferation in response to ethanolinduced liver injury. (HEPATOLOGY 2004;39:721-731.) R ecently, a critical role for TNF␣ in the early pathogenesis of alcohol-induced liver disease has been established. 1 TNF␣ is hypothesized to signal through TNFR1 to initiate a cascade of hepatocellular events, including mitochondrial oxidative stress, activation of stress kinases such as p42/44 and p38, and a number of other responses ultimately leading to cell death. However, TNF␣ has been described as both proapoptotic and mitogenic for hepatocytes. Thus, it is likely that investigation of downstream signal events from the TNF receptor may explain these apparent differences.Ras, a known proto-oncogene, is important in the regulation of cellular responses to TNF␣. Recently, it was shown that TNF␣-mediated signaling in hepatocytes involves activation of the Ras/mitogen activated protein kinase (MAPK) pathway. 2 Inhibition of Ras using a dominant-negative mutant nearly completely inhibited TNF␣-induced hepatocyte proliferation in culture. It has also been shown that TNF␣-mediated hepatocyte proliferation after partial hepatectomy is dependent on Ras activation. 3 Yet, it is unclear whether TNF␣ release caused by chronic eth...

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Ras adenoviruses modulate cyclin E protein expression and DNA synthesis after partial hepatectomy

Cited by 24 publications

References 51 publications

Blunted DNA synthesis and delayed S-phase entry following inhibition of Cdk2 activity in the regenerating rat liver

Blunted DNA synthesis and delayed S-phase entry following inhibition of Cdk2 activity in the regenerating rat liver

Expression of a cyclin E1 isoform in mice is correlated with the quiescent cell cycle status of hepatocytesin vivo

TNF ?-induced ras activation due to ethanol promotes hepatocyte proliferation independently of liver injury in the mouse

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