Cyclin-dependent kinases in neural development and degeneration

Lim, Anthony C.B.; Qi, Robert Z.

doi:10.3233/jad-2003-5409

Cited by 45 publications

(16 citation statements)

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“…This constitutes the process of re-entry in the cell cycle in neurons [22]. However, because neurons do not proliferate on this pathway, the induction of the transcription factor E2F-1 gives another pathway involved in the process of neuronal cell death [23].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Ataxia Telangiectasia-p53-E2F-1 Pathway in Neurons as a Target for the Prevention of Neuronal Apoptosis

Camins

Verdaguer²,

Folch³

et al. 2007

CDM

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Over the last few decades, understanding of the mechanisms involved in the process of neuronal cell death has grown. Recent findings have established that DNA damage, and specifically ataxia telangiectasia mutated protein (ATM), is key to the cascade of regulation of neuronal apoptosis. Another characteristic common to all neurodegenerative diseases is oxidative stress. Likewise, a common feature in the brain of patients with neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and other neurological disorders is the expression of proteins involved in cell-cycle control. In the process of re-entry in the cell cycle, an additional component, transcription factor E2F-1, also involved in the regulation of apoptosis, is expressed. Finally, in this complex puzzle, mitochondrial activation with the release of proteins and the activation of cystein proteases, specifically caspase-3, is prominent in the last step of neuronal apoptosis. This review focuses on the role of ATM activation and its re-entry into the cell cycle in neurons as a potential target for the prevention of neuronal apoptosis. We suggest the mechanisms by which ATM and E2F-1 orchestrate the apoptotic process. Among them, p53 could be a common point on this apoptotic route. Finally, we put forward drugs that are now being studied experimentally, such as p53 inhibitors, ATM inhibitors and cyclin-dependent kinase (CDKs) inhibitors, for the treatment of neurodegenerative diseases.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Ataxia Telangiectasia-p53-E2F-1 Pathway in Neurons as a Target for the Prevention of Neuronal Apoptosis

Camins

Verdaguer²,

Folch³

et al. 2007

CDM

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“…in vitro and also in vivo [16,19]. Moreover, CDK inhibitors have neuroprotective effects in a wide range of experimental neurodegeneration models, and studies performed using the brains of patients suffering from neurodegenerative diseases such as PD, AD, and Huntington's disease have demonstrated an increase in the expression of proteins involved in the cell cycle [21][22][23][24][25][26][27][28][29][30][31]. Interestingly, the possible link between cell-cycle re-entry and neuronal apoptosis could be the transcription factor E2F-1 [32,33].…”

Section: Introductionmentioning

confidence: 99%

Activation of ataxia telangiectasia muted under experimental models and human Parkinson’s disease

Camins

Pizarro

Alvira

et al. 2010

Cell. Mol. Life Sci.

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In the present study we demonstrated that neurotoxin MPP(+)-induced DNA damage is followed by ataxia telangiectasia muted (ATM) activation either in cerebellar granule cells (CGC) or in B65 cell line. In CGC, the selective ATM inhibitor KU-55933 showed neuroprotective effects against MPP(+)-induced neuronal cell loss and apoptosis, lending support to the key role of ATM in experimental models of Parkinson's disease. Likewise, we showed that knockdown of ATM levels in neuroblastoma B65 cells using an ATM-specific siRNA attenuates the phosphorylation of retinoblastoma protein without affecting other cell-cycle proteins involved in the G(0)/G(1) cell-cycle phase. Moreover, we demonstrated DNA damage, in human brain samples of PD patients. These findings support a model in which MPP(+) leads to ATM activation with a subsequent DNA damage response and activation of pRb. Therefore, this study demonstrates a new link between DNA damage by MPP(+) and cell-cycle re-entry through retinoblastoma protein phosphorylation.

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“…In the brain, Cdk5-p35 phosphorylates a number of cytoskeletal proteins that are thought to play important roles in the reassembly of cytoskeletal elements, thereby mediating neurite outgrowth and neuronal migration during the development (11)(12)(13)(14)(15)(16). In addition, there are several lines of evidence implicating aberrant regulation of Cdk5 in neurodegeneration and cell death (17). Indeed, p25, a truncated C-terminal fragment of p35, was found to accumulate in Alzheimer's disease brains; its associated-Cdk5 kinase activity was shown to lead to cytoskeletal disruption, morphological degeneration, and apoptosis (18 -21).…”

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confidence: 99%

Protein Kinase CK2 Is an Inhibitor of the Neuronal Cdk5 Kinase

Lim

Hou

Goh

et al. 2004

Journal of Biological Chemistry

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The complex of Cdk5 and its neuronal activator p35 is a proline-directed Ser/Thr kinase that plays an important role in various neuronal functions. Deregulation of the Cdk5 enzymatic activity was found to associate with a number of neurodegenerative diseases. To search for regulatory factors of Cdk5-p35 in the brain, we developed biochemical affinity isolation using a recombinant protein comprising the N-terminal 149 amino acids of p35. The catalytic ␣-subunit of protein kinase CK2 (formerly known as casein kinase 2) was identified by mass spectrometry from the isolation. The association of CK2 with p35 and Cdk5 was demonstrated, and the CK2-binding sites were delineated in p35. Furthermore, CK2 displayed strong inhibition toward the Cdk5 activation by p35. The Cdk5 inhibition is dissociated from the kinase function of CK2 because the kinase-dead mutant of CK2 displayed the similar Cdk5 inhibitory activity as the wild-type enzyme. Further characterization showed that CK2 blocks the complex formation of Cdk5 and p35. Together, these findings suggest that CK2 acts as an inhibitor of Cdk5 in the brain.Cdk5 was identified independently on the basis of its sequence similarity to the family of Cdks, its interaction with cyclin D, and its protein kinase activity toward a prolinedirected Ser/Thr sequence (1-3). Despite having 60% sequence identity with Cdk1 and Cdk2, a role for Cdk5 in cell cycle regulation has yet to be identified. Nevertheless, Cdk5 has been implicated in the regulation of neuronal differentiation, degeneration, and cytoskeletal dynamics (4). Monomeric Cdk5 shows no enzymatic activity because its activation is dependent on its association with the regulatory subunit p35 or p39, neither of which is a cyclin protein (5-7). Mammalian p35 and p39 are primarily expressed in post-mitotic neurons, thereby restricting Cdk5 activity predominantly to the nervous system (8). Cdk5 and p35 are essential for proper brain development. Mice deficient of Cdk5 or p35 display cell-positioning defects in the cerebral cortex (9, 10). In the brain, Cdk5-p35 phosphorylates a number of cytoskeletal proteins that are thought to play important roles in the reassembly of cytoskeletal elements, thereby mediating neurite outgrowth and neuronal migration during the development (11-16). In addition, there are several lines of evidence implicating aberrant regulation of Cdk5 in neurodegeneration and cell death (17). Indeed, p25, a truncated C-terminal fragment of p35, was found to accumulate in Alzheimer's disease brains; its associated-Cdk5 kinase activity was shown to lead to cytoskeletal disruption, morphological degeneration, and apoptosis (18 -21).Cdk5 is involved in the regulation of many vital functions in the brain and, hence, its activity needs to be tightly controlled in the cells. Upon association with its activator p35 or p39, Cdk5 is regulated through various means, and many of its regulatory properties are distinct from those of the authentic Cdk-cyclin. First, p35 is an unstable protein with a half-life of 20 -30 min ...

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Cyclin-dependent kinases in neural development and degeneration

Cited by 45 publications

References 0 publications

Inhibition of Ataxia Telangiectasia-p53-E2F-1 Pathway in Neurons as a Target for the Prevention of Neuronal Apoptosis

Inhibition of Ataxia Telangiectasia-p53-E2F-1 Pathway in Neurons as a Target for the Prevention of Neuronal Apoptosis

Activation of ataxia telangiectasia muted under experimental models and human Parkinson’s disease

Protein Kinase CK2 Is an Inhibitor of the Neuronal Cdk5 Kinase

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