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

Stärkel, Peter; Saeger, Christine De; Sempoux, Christine; Legrand, E; Leclercq, Isabelle; Horsmans, Yves

doi:10.1038/labinvest.3700245

Cited by 8 publications

(10 citation statements)

References 34 publications

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“…5B), inhibition of DNA synthesis by WY14,643 probably results from the absence of PCNA. Evidence of a relationship between cdk2 and PCNA (Sever-Chroneos et al, 2001;Starkel et al, 2005) supports this argument. Furthermore, the inability to phosphorylate cdk2 in the presence of WY14,643 suggests that this compound may operate through a cdk-activating kinase, a mechanism previously identified for mevastatin (Ukomadu and Dutta, 2003).…”

supporting

confidence: 66%

Peroxisome Proliferator-Activated Receptor α and γ Ligands Differentially Affect Smooth Muscle Cell Proliferation and Migration

Zahradka

Wright²,

Fuerst³

et al. 2006

J Pharmacol Exp Ther

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Peroxisome proliferator-activated receptors (PPARs) ␣ and ␥ are expressed in smooth muscle cells (SMCs). This study was designed to compare the effects of PPAR␣ and PPAR␥ on SMC proliferation and migration and to determine how they operate. Treatment of SMCs from porcine coronary artery revealed that mitogen-stimulated DNA synthesis was blocked by the PPAR␣ ligand 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY14,643) and 15-deoxy-⌬ 12,14 prostaglandin J 2 (15d-PGJ 2 ) (a putative PPAR␥ agonist) but not by the PPAR␥ agonist rosiglitazone or the PPAR␤/␦ ligand 2-methyl-4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-thiazol-5-yl)-methylsulfanyl)phenoxy acetic acid (GW501516). Inhibition of DNA synthesis by clofibrate and 2-(4-(2-(1-cyclohexanebutyl-3-cyclohexylureido)ethyl)phenylthio)-2-methylproprionic acid (GW7647) confirmed that SMC proliferation is affected by PPAR␣. This conclusion was supported by the fact that WY14,643 also inhibited the proliferation of H4IIE hepatoma cells (expressing only PPAR␣) but not A10 SMCs (expressing only PPAR␥1). In contrast, the effective inhibition of all cell types with 15d-PGJ 2 indicated that this compound probably operates via a PPAR␥-independent mechanism. Interestingly, rosiglitazone did not inhibit DNA synthesis of either H4IIE or A10 cells, suggesting that the activation of PPAR␥ does not influence cell proliferation. Phosphorylation of cyclin-dependent kinase 2 and expression of proliferating cell nuclear antigen were inhibited by WY14,643 but not by rosiglitazone or 15d-PGJ 2 , indicating that PPAR␣ prevents progression into S phase. Although rosiglitazone did not block SMC proliferation, it (like WY14,643) reduced neointimal hyperplasia in vitro. This observation can be rationalized by the fact that both WY14,643 and rosiglitazone inhibit SMC migration, probably through matrix metalloproteinase 9. Our study therefore shows that selective interference with mediators of cell cycle progression and cell migration via activation of PPARs may prevent growth-related vascular diseases such as restenosis and atherosclerosis.

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supporting

confidence: 66%

Peroxisome Proliferator-Activated Receptor α and γ Ligands Differentially Affect Smooth Muscle Cell Proliferation and Migration

Zahradka

Wright²,

Fuerst³

et al. 2006

J Pharmacol Exp Ther

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“…In addition, interference with Ras gene expression also reduced liver regeneration, presumably through reduction of cyclin E/Cdk2 expression [13]. Our results of strongly reduced liver cell proliferation using the Cdk2 inhibitor roscovitine [35] and the Ras inhibitor FTS in the present study adds further evidence for a critical role of the Ras-cyclin E/Cdk2 axis in hepatocyte proliferation. It has been suggested that Ras signalling via the MAPK pathway may be important in this process.…”

Section: Discussionsupporting

confidence: 57%

“…As shown previously by our group [35], Ckd2 kinase activity is essential for transition from G 1 -to S-phase and inhibition or reduction in its activity blocked hepatocytes in late G 1 -phase. It has been shown that Ras expression increases at a critical time point in the regenerating rat liver [10,36].…”

Section: Discussionmentioning

confidence: 50%

Inhibition of the Ras oncoprotein reduces proliferation of hepatocytes in vitro and in vivo in rats

et al. 2007

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Ras oncoproteins are probably implicated in normal and malignant cell growth in various organs. Inhibition of Ras interferes with cell proliferation of non-hepatic cells in vitro and in vivo. A potential role for Ras in normal and malignant hepatocyte proliferation prompted us to evaluate the impact of Ras inhibition by FTS (S-farnesylthiosalicylic acid) on hepatocyte proliferation in vitro in the human hepatic tumour cell line HepG2 and in vivo after PH (partial hepatectomy) in rats. Rats were administered with FTS intraperitoneally (1, 8 and 16 h after PH) and killed 12, 24 and 48 h after PH. Cell proliferation, phosphorlyation of members of the MAPK (mitogen-activated protein kinase) pathway and levels and activity of cell cycle effectors (cyclin D, cyclin E, Cdk2 and Cdk4) were assessed in FTS-treated rats compared with controls. FTS significantly decreased overall cell count, PCNA (proliferating-cell nuclear antigen) expression and BrdU (bromodeoxyuridine) incorporation into HepG2 cells after 7 days of culture. FTS treatment significantly reduced BrdU incorporation and PCNA expression in hepatocytes after PH. Unlike control rats, cell-membrane expression of Ras was decreased in FTS-treated animals after PH, resulting in decreased Raf membrane recruitment and phosphorylation and in reduced phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2). The antiproliferative effect of FTS was linked to a decrease in expression and activity of the cyclin E/Cdk2 complex, without affecting cyclin D and Cdk4. Ras inhibition by FTS significantly decreased proliferation of HepG2 cells and normal hepatocytes after a strong and highly synchronized proliferation stimulus elicited by PH. The inhibitory effect was at least partially mediated by inhibition of Ras/Raf/MAPK signalling. It appears worthwhile to evaluate the impact of Ras inhibition on the development of hepatocarcinomas in vivo in adequate animal models.

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“…Although we did not perform a full time course of liver regeneration in the cdk2 -/- mice, a previous study has demonstrated that seliciclib impairs hepatocyte proliferation after PH. 29 Of note, another recent study found no difference in DNA synthesis at later time points after PH (48–72 hr) between cdk2 -/- and WT mice. 35 The combined data suggests that the absence of cdk2 delays but does not prevent the onset of DNA synthesis in this model, compatible with the observation that liver regeneration is driven by alternative mechanisms when one or more pathway is interrupted.…”

Section: Discussionmentioning

confidence: 92%

“…1,2 A prior study has shown that treatment with seliciclib diminishes hepatocyte proliferation after PH, 29 suggesting that cdk2 plays a role in liver regeneration. However, this drug has several targets aside from cdk2.…”

Section: Resultsmentioning

confidence: 99%

Cdk2 plays a critical role in hepatocyte cell cycle progression and survival in the setting of cyclin D1 expression in vivo

Hanse¹,

Nelsen²,

Goggin³

et al. 2009

Cell Cycle

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Cdk2 was once believed to play an essential role in cell cycle progression, but cdk2-/- mice have minimal phenotypic abnormalities. In this study, we examined the role of cdk2 in hepatocyte proliferation, centrosome duplication and survival. Cdk2-/- hepatocytes underwent mitosis and had normal centrosome content after mitogen stimulation. Unlike wild-type cells, cdk2-/- liver cells failed to undergo centrosome overduplication in response to ectopic cyclin D1 expression. After mitogen stimulation in culture or partial hepatectomy in vivo, cdk2-/- hepatocytes demonstrated diminished proliferation. Cyclin D1 is a key mediator of cell cycle progression in hepatocytes, and transient expression of this protein is sufficient to promote robust proliferation of these cells in vivo. In cdk2-/- mice and animals treated with the cdk2 inhibitor seliciclib, cyclin D1 failed to induce hepatocyte cell cycle progression. Surprisingly, cdk2 ablation or inhibition led to massive hepatocyte and animal death following cyclin D1 transfection. In a transgenic model of chronic hepatic cyclin D1 expression, seliciclib induced hepatocyte injury and animal death, suggesting that cdk2 is required for survival of cyclin D1-expressing cells even in the absence of substantial proliferation. In conclusion, our studies demonstrate that cdk2 plays a role in liver regeneration. Furthermore, it is essential for centrosome overduplication, proliferation and survival of hepatocytes that aberrantly express cyclin D1 in vivo. These studies suggest that cdk2 may warrant further investigation as a target for therapy of liver tumors with constitutive cyclin D1 expression.

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

Cited by 8 publications

References 34 publications

Peroxisome Proliferator-Activated Receptor α and γ Ligands Differentially Affect Smooth Muscle Cell Proliferation and Migration

Peroxisome Proliferator-Activated Receptor α and γ Ligands Differentially Affect Smooth Muscle Cell Proliferation and Migration

Inhibition of the Ras oncoprotein reduces proliferation of hepatocytes in vitro and in vivo in rats

Cdk2 plays a critical role in hepatocyte cell cycle progression and survival in the setting of cyclin D1 expression in vivo

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