Article

Cyclin-Dependent Kinase 5 Is Essential for Neuronal Cell Cycle Arrest and Differentiation

Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 11/2005; 25(42):9658-68. DOI: 10.1523/JNEUROSCI.1773-05.2005
Source: PubMed

ABSTRACT Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase with significant homology to cell cycle-related Cdks but is not believed to be active in a typical cell cycle. In Cdk5-deficient embryos and Cdk5 chimeras, migration and survival of postmitotic neurons is compromised in a cell-autonomous manner. In the present study, we show that loss of Cdk5 leads to both failure of neuronal differentiation and loss of cell cycle control. Using specific cytoskeletal proteins as indices of neuronal differentiation, we find that Cdk5-deficient neurons are significantly arrested or delayed in their developmental program both in vivo and in vitro. For example, immunocytochemistry of embryonic day 16 (E16) cortex reveals that the expression of microtubule-associated protein 2c (Map-2c), a marker of mature neurons, is nearly absent in Cdk5(-/-) cells that have migrated to the cortical plate while these same cells continue to express nestin. Similarly, in vitro, Map-2-positive cells are rare in cultures from E16 Cdk5(-/-) embryos. Cell cycle control is also deficient in Cdk5(-/-) cells. In vivo, neurons engaged in cell cycle activities are found in the cortical plate, and, in vitro, class III beta-tubulin-positive cells continue to label with bromodeoxyuridine even after 5 d of incubation. Transfection of a wild-type Cdk5 construct reveals that cell cycle control can be regained in Cdk5(-/-) cells by overexpression of Cdk5. These data indicate that Cdk5 is necessary for both neuronal differentiation and cell cycle inhibition.

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    • "CDK5 phosphorylates NFs directly and also phosphorylates MT-associated proteins such as MAP2, MAP1b, and Tau, which induces the formation and stability of MTs when phosphorylated. CDK5 also regulates the NUDEL protein, which is associated with dynein motor activity (Ohshima et al., 1996; Niethammer et al., 2000; Cicero and Herrup, 2005; Zheng et al., 2007). "
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    Frontiers in Aging Neuroscience 09/2014; 6:232. DOI:10.3389/fnagi.2014.00232 · 2.84 Impact Factor
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    • "A common consequence of targeted cancer therapeutics in rapidly dividing bulk tumor cells is the ability of a compound to arrest cell division, usually leading to either differentiation or apoptosis. Interestingly, in the case of neurodegenerative pathways associated with CDK5 activation, there is often transient reactivation of cell cycle machinery directly preceding neuronal cell death (Cicero et al., 2005). Therefore, anticancer compounds that modulate the cell cycle may be active even in typically nondividing cells of the brain, and furthermore the differentiation-promoting effects may support production of mature neuronal progeny from endogenous regions of neurogenesis. "
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    • "CDK5 does not appear to have a major role in cell cycle regulation (3,4). It has been well characterized for its dominant role in the development of the central nervous system, including roles in neuronal migration, differentiation and adhesion (5,6). We and others subsequently showed that CDK5 plays an important role in cancer development and metastasis (7–12). "
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