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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    ABSTRACT: Alzheimer's disease (AD) is the most common cause of dementia worldwide. One of the main pathological changes that occurs in AD is the intracellular accumulation of hyperphosphorylated Tau protein in neurons. Cyclin-dependent kinase 5 (CDK5) is one of the major kinases involved in Tau phosphorylation, directly phosphorylating various residues and simultaneously regulating various substrates such as kinases and phosphatases that influence Tau phosphorylation in a synergistic and antagonistic way. It remains unknown how the interaction between CDK5 and its substrates promotes Tau phosphorylation, and systemic approaches are needed that allow an analysis of all the proteins involved. In this review, the role of the CDK5 signaling pathway in Tau hyperphosphorylation is described, an in silico model of the CDK5 signaling pathway is presented. The relationship among these theoretical and computational models shows that the regulation of Tau phosphorylation by PP2A and glycogen synthase kinase 3β (GSK3β) is essential under basal conditions and also describes the leading role of CDK5 under excitotoxic conditions, where silencing of CDK5 can generate changes in these enzymes to reverse a pathological condition that simulates AD.
    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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    ABSTRACT: Background and purposeAnti-retrovirals have improved and extended the life expectancy of patients with human immunodeficiency virus (HIV). However, as this population ages, the prevalence of cognitive alterations is increasing. Aberrant activation of kinases, such as receptor tyrosine kinases (RTKs) and cyclin dependent kinase 5 (CDK5) play a role in the mechanisms of HIV neurotoxicity. Inhibitors of CDK5, such as roscovitine, have neuroprotective effects, however CNS penetration is low. Interestingly, tyrosine kinase inhibitors (TKIs) display some CDK inhibitory activity and ability to cross the blood-brain barrier.Experimental approachWe screened a small group of known TKIs for a candidate with additional CDK5 inhibitory activity and tested the efficacy of the candidate in in vitro and in vivo models of HIV-gp120 neurotoxicity.Key resultsAmong 12 different compounds, sunitinib inhibited CDK5 with an IC50 of 4.2 μM. In silico analysis revealed that, similarly to roscovitine, sunitinib fitted 6 of 10 features of the CDK5 pharmacophore. In a cell-based model, sunitinib reduced CDK5 phosphorylation (pCDK5), calpain-dependent p35/p25 conversion and protected neuronal cells from the toxic effects of gp120. In GFAP-gp120 transgenic mice, sunitinib reduced levels of pCDK5, p35/p25, phosphorylated Tau, as well as ameliorated the neurodegenerative pathology, and promoted in gp120 tg mice.Conclusions & implicationsThis study supports the notion that compounds such as sunitinib with dual kinase inhibitory activity might ameliorate the cognitive impairments associated with the chronic HIV involvement of the CNS. Moreover, repositioning existing small molecule compounds holds promise for the treatment of patients with neurodegenerative disorders.
    British Journal of Pharmacology 08/2014; 171(24). DOI:10.1111/bph.12875 · 4.99 Impact Factor
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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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    ABSTRACT: Cyclin-dependent kinase 5 (CDK5) is a potential target for prostate cancer treatment, the enzyme being essential for prostate tumor growth and formation of metastases. In the present study, we identified agents that target prostate cancer cells based on CDK5 expression. CDK5 activity was suppressed by transfection of PC3 prostate cancer cells with a dominant-negative construct (PC3 CDK5dn). PC3 CDK5dn and PC3 control cells were screened for compounds that selectively target cells based on CDK5 expression, utilizing the Johns Hopkins Drug Library. MTS proliferation, clonogenic and 3D growth assays were performed to validate the selected hits. Screening of 3,360 compounds identified rutilantin, ethacridine lactate and cetalkonium chloride as compounds that selectively target PC3 control cells and a tilorone analog as a selective inhibitor of PC3 CDK5dn cells. A PubMed literature study indicated that tilorone may have clinical use in patients. Validation experiments confirmed that tilorone treatment resulted in decreased PC3 cell growth and invasion; PC3 cells with inactive CDK5 were inhibited more effectively. Future studies are needed to unravel the mechanism of action of tilorone in CDK5 deficient prostate cancer cells and to test combination therapies with tilorone and a CDK5 inhibitor for its potential use in clinical practice.
    Oncology Reports 05/2014; 32(1). DOI:10.3892/or.2014.3174 · 2.19 Impact Factor
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