Antiproliferative action of valproate is associated with aberrant expression and nuclear translocation of cyclin D3 during the C6 glioma G1 phase

Cell cycle progression is tightly regulated by cyclins, cyclin‐dependent kinases (cdks) and related inhibitory phophatases. Here, we employed mitotic selection to synchronize the C6 glioma cell cycle at the start of the G1 phase and mapped the temporal regulation of selected cyclins, cdks and inhibi...

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Bibliographic Details
Published in:Journal of neurochemistry 2002-10, Vol.83 (1), p.12-19
Main Authors: Bacon, Christopher L., Gallagher, Helen C., Haughey, John C., Regan, Ciaran M.
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus - drug effects
Animals
anticonvulsant
Anticonvulsants - pharmacology
Biological and medical sciences
cell cycle
Cell Cycle - drug effects
Cell Cycle - physiology
Cell Cycle Proteins - metabolism
Cell cycle, cell proliferation
Cell Division - drug effects
Cell Line
Cell Nucleus - metabolism
Cell physiology
Cyclin D1 - metabolism
Cyclin D3
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase Inhibitor p27
Cyclin-Dependent Kinases - metabolism
Cyclins - metabolism
Dose-Response Relationship, Drug
Fundamental and applied biological sciences. Psychology
G1 Phase - drug effects
Glioma - drug therapy
Glioma - metabolism
Glioma - pathology
Immunoblotting
Immunohistochemistry
mitotic selection
Molecular and cellular biology
Proliferating Cell Nuclear Antigen - metabolism
Proto-Oncogene Proteins
Rats
synchronization
teratogen
Tumor Suppressor Proteins - metabolism
valproic acid
Valproic Acid - pharmacology
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Summary:Cell cycle progression is tightly regulated by cyclins, cyclin‐dependent kinases (cdks) and related inhibitory phophatases. Here, we employed mitotic selection to synchronize the C6 glioma cell cycle at the start of the G1 phase and mapped the temporal regulation of selected cyclins, cdks and inhibitory proteins throughout the 12 h of G1 by immunoblot analysis. The D‐type cyclins, D3 and D1, were differentially expressed during the C6 glioma G1 phase. Cyclin D1 was up‐regulated in the mid‐G1 phase (4–6 h) while cyclin D3 expression emerged only in late G1 (9–12 h). The influence of the anticonvulsant agent valproic acid (VPA) on expression of cyclins and related proteins was determined, since its teratogenic potency has been linked to cell cycle arrest in the mid‐G1 phase. Exposure of C6 glioma to VPA induced a marked up‐regulation of cyclin D3 and decreased expression of the proliferating cell nuclear antigen. In synchronized cell populations, increased expression of cyclin D3 by VPA was detected in the mid‐G1 phase (3–5 h). Immunocytochemical localization demonstrated rapid intracellular translocation of cyclin D3 to the nucleus following VPA exposure, suggesting that VPA‐induced cell cycle arrest may be mediated by precocious activation of cyclin D3 in the G1 phase.
ISSN:0022-3042
1471-4159
DOI:10.1046/j.1471-4159.2002.01081.x