CDK2 regulation through PI3K and CDK4 is necessary for cell cycle progression of primary rat hepatocytes

Wierød, Lene; Rosseland, Carola M.; Lindeman, Birgitte; Oksvold, Morten P.; Grøsvik, H.; Skarpen, Ellen; Huitfeldt, Henrik S.

doi:10.1111/j.1365-2184.2007.00451.x

Cited by 26 publications

(18 citation statements)

References 46 publications

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“…As also observed previously, cyclin D1 was induced from 18 hours after EGF stimulation, and remained high through the period where EGF receptor activation was very low (Fig. 1C and D) [4]. Cyclin E was present and unaffected by EGF stimulation through the studied period.…”

Section: Resultssupporting

confidence: 61%

“…Growth factor activation of Cdk2 and Cdk4 drives the cell cycle progression until a checkpoint in late G 1 . In primary hepatocytes, cyclin E appears to be induced by cell isolation or plating and is thereafter unaffected by growth factor addition [4]. Induction of cyclin D1 through Erk1/2 and PI3K signaling appears to be the main, growth factor regulated event leading to pRb hyperphosphorylation [3,4].…”

Section: Resultsmentioning

confidence: 99%

“…In primary hepatocytes, cyclin E appears to be induced by cell isolation or plating and is thereafter unaffected by growth factor addition [4]. Induction of cyclin D1 through Erk1/2 and PI3K signaling appears to be the main, growth factor regulated event leading to pRb hyperphosphorylation [3,4]. To correlate G 1 cyclin induction with EGF receptor activation and signaling, we studied the time course of cyclin E and D1 expression following EGF stimulation.…”

Section: Resultsmentioning

confidence: 99%

“…In such cultures, priming and cyclin E induction are achieved at hepatocyte isolation and plating, whereas cyclin D1 expression is strictly regulated by EGF, TGFα and HGF. These growth factors bind to and activate their respective receptors; EGF receptor or c-Met [3,4]. D-type cyclins appear to act as intracellular “sensors” of extracellular stimuli that promote proliferation [5,6].…”

Section: Introductionmentioning

confidence: 99%

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EGF Activates Autocrine TGFα to Induce Prolonged EGF Receptor Signaling and Hepatocyte Proliferation

Liu

Wierød

Skarpen

et al. 2013

Cell Physiol Biochem

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Background/Aims: EGF receptor is a main participant in the regulation of liver regeneration. In primary hepatocyte cultures, EGF or TGFα binding to EGF receptor activates Erk1/2 and PI3K pathways, induces cyclin D1 and thus initiates DNA synthesis. We have explored mechanisms by which prolonged EGF receptor activation induces hepatocyte proliferation. Methods: EGF receptor activation, as well as Erk1/2 and PI3K signaling were explored in EGF-stimulated primary hepatocyte cultures by Western blotting and immunocytochemistry. TGFα release to the medium was quantified by ELISA. Effects of a neutralizing antibody to TGFα on EGF receptor signaling and proliferation were explored. Results: Inhibitors of PI3K or Erk1/2 inhibited cyclin D1 expression and G₁ progression when added 12 hours after EGF stimulation, whereas depletion of EGF from the medium at this time point did not. ELISA demonstrated that EGF induced TGFα release to the medium. Cyclin D1 induction and cellular proliferation were efficiently inhibited when a neutralizing antibody to TGFα was added to the medium. This also occurred when the antibody was added 12 hours after EGF stimulation. Conclusion: Sustained EGF receptor activity and signaling through both Erk1/2 and PI3K pathways were necessary for proliferation. This was achieved by EGF activation of autocrine TGFα.

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Section: Resultssupporting

confidence: 61%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

EGF Activates Autocrine TGFα to Induce Prolonged EGF Receptor Signaling and Hepatocyte Proliferation

Liu

Wierød

Skarpen

et al. 2013

Cell Physiol Biochem

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“…Activation of the PI3K pathway promotes the nuclear translocation of CDK2 and phosphorylation of CDK2 at T160 in activation site [97]. Activated CDK2 in turn phosphorylates ERα at S294 and mediates Pin1-ERα interaction, which increases ERK-dependent ERα phosphorylation at S118 and S167 in the transcriptional activation function domain and promotes ERα dimerization and activity [98,99].…”

Section: Pin1 Regulates Nuclear Receptorsmentioning

confidence: 99%

Prolyl isomerase Pin1 in cancer

2014

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Proline-directed phosphorylation is a posttranslational modification that is instrumental in regulating signaling from the plasma membrane to the nucleus, and its dysregulation contributes to cancer development. Protein interacting with never in mitosis A1 (Pin1), which is overexpressed in many types of cancer, isomerizes specific phosphorylated Ser/Thr-Pro bonds in many substrate proteins, including glycolytic enzyme, protein kinases, protein phosphatases, methyltransferase, lipid kinase, ubiquitin E3 ligase, DNA endonuclease, RNA polymerase, and transcription activators and regulators. This Pin1-mediated isomerization alters the structures and activities of these proteins, thereby regulating cell metabolism, cell mobility, cell cycle progression, cell proliferation, cell survival, apoptosis and tumor development.

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Involvement of PI3K/Akt pathway in the protective effect of hesperidin against a chemically induced liver cancer in rats

Mo’men

Hussein

Kandeil

2019

J Biochem & Molecular Tox

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Hesperidin is a flavanone glycoside that is found in the Citrus species and showed antioxidant, hepatoprotective as well as anticancer activity. This study investigated the effect of hesperidin on the PI3K/Akt pathway as a possible mechanism for its protective effect against diethylnitrosamine (DEN)‐induced hepatocellular carcinoma (HCC). Adult Wistar rats were divided into Control group (received drug vehicle); DEN group (received 100 mg/L of DEN solution for 8 weeks), and hesperidin + DEN group (received 200 mg/kg body weight of hesperidin/day orally for 16 weeks + DEN solution as DEN group). Our findings showed that the administration of hesperidin significantly decreased the elevation in liver function enzymes, serum AFP level, and oxidative stress markers. Moreover, hesperidin administration suppressed DEN‐induced upregulation of PI3K, Akt, CDK‐2 protein expression, and preserved the integrity of the liver tissues from HCC formation. In conclusion, the hepatoprotective activity of hesperidin is mediated via its antioxidation and downregulation of the PI3K/Akt pathway.

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CDK2 regulation through PI3K and CDK4 is necessary for cell cycle progression of primary rat hepatocytes

Cited by 26 publications

References 46 publications

EGF Activates Autocrine TGFα to Induce Prolonged EGF Receptor Signaling and Hepatocyte Proliferation

EGF Activates Autocrine TGFα to Induce Prolonged EGF Receptor Signaling and Hepatocyte Proliferation

Prolyl isomerase Pin1 in cancer

Involvement of PI3K/Akt pathway in the protective effect of hesperidin against a chemically induced liver cancer in rats

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