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The Journal of Neuroscience, February 15, 2001, 21(4):1274-1282

Inhibition of Cyclin E-Cyclin-Dependent Kinase 2 Complex Formation and Activity Is Associated with Cell Cycle Arrest and Withdrawal in Oligodendrocyte Progenitor Cells

Cristina A. Ghiani and Vittorio Gallo

Laboratory of Cellular and Molecular Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4495

Stimulatory and inhibitory signals regulate cell proliferation through the activity of specific enzymes that operate in distinct phases of the cell cycle. We have studied cell cycle progression, arrest, and withdrawal in the oligodendrocyte progenitor (OP) cell model system, focusing on the G₁ phase and G₁-S transition. Not only were proliferating OPs found to display higher protein levels of cyclin E and D and cyclin-dependent kinases (cdk) 2, 4, and 6 than cells that had permanently withdrawn from the cycle, but the kinase activities of both cyclin D-cdk4/6 and cyclin E-cdk2 were also higher in dividing OPs. This was associated with a decrease in the formation of the cyclin E-cdk2 and cyclin D-cdk4/cyclin D-cdk6 complexes in differentiated oligodendrocytes that had permanently withdrawn from the cell cycle. Reversible cell cycle arrest in G₁ induced by glutamatergic and -adrenergic receptor activation or cell depolarization, however, did not modify cyclin E and cdk2 protein expression compared with proliferating OPs. Instead, these agents caused a selective decrease in cdk2 activity and an impairment of cyclin E-cdk2 complex formation. Although cyclin D protein levels were higher than in proliferating cells, cyclin D-associated kinase activity was not modified in G₁-arrested OPs. Analysis in corpus callosum in vivo showed that cyclin E-cdk2 activity increased between postnatal days 3 and 15 and decreased between postnatal days 15 and 30. Our results indicate that the cyclin E-cdk2 complex is a major regulator of OP cell cycle progression and that the cdks involved in reversible cell cycle arrest are distinct from those implicated in permanent cell cycle withdrawal.

Key words: glia; development; cell proliferation; G₁ phase; cyclin D; cyclin-dependent kinase 4

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2141274-09$05.00/0

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