Induction of UGT1A1 and CYP2B6 by an antimitogenic factor in HepG2 cells is mediated through suppression of cyclin-dependent kinase 2 activity: Cell-cycle dependent expression
| Autor: | Junko Sugatani, Masatoshi Kurosawa, Naomi Kitamura, Masao Miwa, Makoto Osabe, Akira Ikari |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Small interfering RNA
Receptors Steroid Pharmaceutical Science Gene Expression Receptors Cytoplasmic and Nuclear Histones Phosphatidylinositol 3-Kinases Cytochrome P-450 CYP3A Glucuronosyltransferase Phosphorylation RNA Small Interfering Extracellular Signal-Regulated MAP Kinases Cyclin-Dependent Kinase Inhibitor Proteins Phosphoinositide-3 Kinase Inhibitors biology Hepatocyte Growth Factor Cell Cycle Pregnane X Receptor Transfection Hep G2 Cells Cyclin-Dependent Kinases Gene Expression Regulation Neoplastic Enzyme Induction Intercellular Signaling Peptides and Proteins Hepatocyte growth factor Aryl Hydrocarbon Hydroxylases Signal transduction medicine.drug Signal Transduction digestive system Cyclin-dependent kinase Cell Line Tumor medicine Cytochrome P-450 CYP1A1 Roscovitine Humans Protein Kinase Inhibitors Cell Proliferation Pharmacology Cyclin-dependent kinase 2 Cyclin-Dependent Kinase 2 JNK Mitogen-Activated Protein Kinases Oxidoreductases N-Demethylating Molecular biology digestive system diseases Cytochrome P-450 CYP2B6 Cell culture Purines biology.protein CDK inhibitor |
| Zdroj: | Drug Metab. Dispos.. 38:177-186 |
| Popis: | Hepatocyte growth factor (HGF), an antimitogenic factor for HepG2 cells, increased mRNA and protein levels of UGT1A1 and CYP2B6, as well as the endogenous cyclin-dependent kinase (CDK) inhibitors p16, p21, and p27 in HepG2 cells but not in HuH6, Caco2, or MCF7 cells. Treatment with 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126) (an extracellular signal-regulated kinase inhibitor) suppressed the HGF-induced expression of UGT1A1 and CYP2B6, as well as p16, p21, and p27 in HepG2 cells. The CDK inhibitor roscovitine also enhanced the expression of UGT1A1, CYP2B6, and CYP3A4. Transfection of anti-CDK2 siRNA led to elevated levels of UGT1A1, CYP2B6, and CYP3A4 in HepG2 and SW480 cells, whereas anti-CDK4 small interfering RNA (siRNA) did not significantly enhance the expression of these enzymes. In fact, CDK2 activity was decreased in HGF-treated HepG2 cells. In cells arrested in S phase by a thymidine block and then released into a synchronous cell cycle, there was a clear dissociation among the activation of CDK2 and the expression of UGT1A1, CYP2B6, and CYP3A4. Furthermore, the induction of CYP3A4 but not UGT1A1 or CYP2B6 mRNA expression by roscovitine was repressed in pregnane X receptor (PXR) siRNA-transfected HepG2 cells. Transfection with constitutive androstane receptor siRNA or PXR siRNA in HepG2 cells did not repress the HGF-stimulated expression of UGT1A1 mRNA. Taken together, our results show that the expression of UGT1A1 and CYP2B6 is negatively regulated through a CDK2 signaling pathway linked to cell cycle progression in HepG2 and SW480 cells, the mechanism of which may differ from that of CYP3A4 expression through PXR phosphorylated by CDK2. |
| Databáze: | OpenAIRE |
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