Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclin-dependent kinase 5 (Cdk5) is a unique member of the CDK family. It is predominantly expressed in postmitotic neurons and has been implicated in neuronal plasticity. The present study showed that Cdk5 and p35 were expressed in primary sensory and dorsal horn neurons, while p25, an N-terminal truncated derivative of p35, could only be detected in the dorsal horn neurons. Importantly, in the case of control rats, the p35 protein level was much higher in small- and medium-diameter DRG neurons than it was in large neurons. Following CFA injection, Cdk5 activity was upregulated in both primary sensory and dorsal horn neurons. Cdk5 activation in DRG neurons required p35, whereas p25 was required in the dorsal horn. Intrathecal pretreatment with Roscovitine, a specific inhibitor of Cdk5 activity, and intrathecal delivery of the DN-Cdk5(N144) gene both alleviated CFA-induced heat hyperalgesia but not mechanical allodynia. In contrast, overexpression of Cdk5, p35 or p25 in primary sensory and dorsal horn neurons significantly enhanced heat hyperalgesia. We conclude that Cdk5/p35 and Cdk5/p25 complexes in primary sensory and dorsal horn neurons may potentially be involved in nociceptive transmission after inflammation and may be employed in synaptic plasticity underlying pain hypersensitization.
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PMID:Activation of cyclin-dependent kinase 5 (Cdk5) in primary sensory and dorsal horn neurons by peripheral inflammation contributes to heat hyperalgesia. 1699 90

Interests in CDK2 and CDK5 have stemmed mainly from their association with cancer and neuronal migration or differentiation related diseases and the need to design selective inhibitors for these kinases. Molecular dynamics (MD) simulations have not only become a viable approach to drug design because of advances in computer technology but are increasingly an integral part of drug discovery processes. It is common in MD simulations of inhibitor/CDK complexes to exclude the activator of the CDKs in the structural models to keep computational time tractable. In this paper, we present simulation results of CDK2 and CDK5 with roscovitine using models with and without their activators (cyclinA and p25). While p25 was found to induce slight changes in CDK5, the calculations support that cyclinA leads to significant conformational changes near the active site of CDK2. This suggests that detailed and structure-based inhibitor design targeted at these CDKs should employ activator-included models of the kinases. Comparisons between P/CDK2/cyclinA/roscovitine and CDK5/p25/roscovitine complexes reveal differences in the conformations of the glutamine around the active sites, which may be exploited to find highly selective inhibitors with respect to CDK2 and CDK5.
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PMID:Molecular dynamics simulations on the inhibition of cyclin-dependent kinases 2 and 5 in the presence of activators. 1705 19

Roscovitine, a purine analogue, has been considered for the treatment of cancer. Anti-cancer therapeutic efficacy is being evaluated in clinical trials. However, the mechanisms remain unclear. In the present study, cyclic-dependent kinase 5 (cdk5) proved to be a molecular target for roscovitine-triggered apoptosis for highly invasive breast cancer cell death. Because our previous studies have shown a potential role of cdk5 in endothelial cell proliferation/apoptosis [Sharma, M.R., Tuszynski, G.P., Sharma, M.C. (2004). Angiostatin-induced inhibition of endothelial cell proliferation/apoptosis is associated with the down-regulation of cell cycle regulatory protein cdk5. J. Cell Biochem. 91, 398-409], here we not only demonstrate first that Cdk5, p35, and p25 proteins were all expressed in invasive breast cancer cells MDA-MB231 but also showed that cdk5 expression regulates MDA-MB231 cell proliferation. In addition, potent mitogen bFGF up-regulates cdk5 expression. Roscovitine specifically inhibits cdk5 expression/activity in a dose-dependent manner with concomitant inhibition of MDA-MB231 cell proliferation and induction of apoptosis. By contrast, the roscovitine analog olomoucine, a specific inhibitor of cdk4, failed to affect MDA-MB231 cell proliferation and apoptosis which implies the specific involvement of cdk5 in roscovitine-triggered cell death/proliferation. Additionally, roscovitine-mediated inhibition of proliferation is irreversible. These data suggest that cdk5 may have a significant role in the regulation of breast cancer cell proliferation and apoptosis and extend beyond its role in neurogenesis. These results suggest that Cdk5 is a novel player in roscovitine-triggered breast cancer cell apoptosis and inhibition of proliferation, therefore, may be a potential therapeutic target.
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PMID:Roscovitine regulates invasive breast cancer cell (MDA-MB231) proliferation and survival through cell cycle regulatory protein cdk5. 1708 16

Acute treatment with kainate 30 mg/kg (KA) produced behavioral alterations and reactive gliosis. However, it did not produce major death of mouse hippocampal neurons, indicating that concentrations were not cytotoxic. KA caused rapid and temporal Erk phosphorylation (at 6h) and Akt dephosphorylation (1-3 days). Concomitantly, the activation of GSK3beta was increased 1-3 days after KA. After 7 days, a reduction in GSK3beta activation was observed. Caspase-3 activity increased, but to a lesser extent than calpain activation (measured by fluorimetry and calpain-cleaved alpha-spectrin). As calpain is involved in cdk5 activation, and cdk5 is related to GSK3beta, the cdk5/p25 pathway was examined. Results showed that the p25/p35 ratio in KA-injected mice for 3 days was 73.6% higher than control levels. However, no changes in cdk5 expression were detected. Both Western blot and immunohistochemistry against p-Tau(Thr(231)) indicated an increase at this phosphorylated site of tau protein. Indeed an increase in p-Tau(Ser(199)) and p-Tau(Ser(396)) was observed by Western blot. Our results demonstrate that tau hyperphosphorylation, induced by KA, is due to an increase in GSK3beta/cdk5 activity in combination with an inactivation of Akt. This indicates that the calpain/cdk5 pathway for tau phosphorylation has a potential role in delayed apoptotic death evoked by excitotoxicity. Moreover, the subsequent activation of caspase and calpain proteases leads to dephosphorylation of tau, thus increasing microtubular destructuration. Taken together, our results provide new insights in the activation of several kinase-pathways implicated in cytoskeletal alterations that are a common feature of neurodegenerative diseases.
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PMID:Kainate induces AKT, ERK and cdk5/GSK3beta pathway deregulation, phosphorylates tau protein in mouse hippocampus. 1711 46

Cdk5 is an atypical cyclin-dependent kinase localized in the brain, and its activity is dependent upon binding to p35/p39. In addition, while cdk5 has important physiological functions related to brain development, the breakdown of cdk5/p35 into cdk5/p25 increases its kinase activity and neurotoxicity. Interestingly, in recent years increased cdk5/p25 expression has been demonstrated in the brains of patients with Alzheimer's and Parkinson's diseases. Experimental studies performed in neuronal cell cultures indicate that cdk5/p25 plays a prominent role in apoptosis. Moreover, an apoptotic pathway, via an intracellular calcium increase following calpain activation and cdk5/p25 formation, has been postulated. Cdk5/p25 subsequently phosphorylates the nuclear transcription factor myocyte enhancer factor (MEF2), thereby inhibiting its prosurvival activity. However, cdk5/p25 could phosphorylate other substrates such as tau and p53, as well as the retinoblastoma protein pRb. All these data lend credence to the hypothesis that cdk5/p25 acts as a master regulator of neuronal cell death. In addition, cdk5/p25 might also interact with other pathways such as glycogen synthetase kinase 3beta (GSK3beta) and c-JUN kinase. Drugs like roscovitine, flavopiridol, calpain inhibitors, kenpaullone and induribins, which inhibit cdk5/p25 formation, constitute potential drugs for the treatment of neurological disorders. Furthermore, the dual inhibitory effect of some of these drugs on cdk5 and GSK3beta could be beneficial.
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PMID:The role of CDK5/P25 formation/inhibition in neurodegeneration. 1716 Jan 45

A novel clubbed triazolyl thiazole series of cdk5/p25 inhibitors, potentially useful for the treatment of Alzheimer's disease, is disclosed. Evaluation of the SAR of substitution within these series has allowed the identification of a range of compounds which significantly reduce brain cdk5/p25 and thus have potential as possible treatments for Alzheimer's disease.
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PMID:Clubbed thiazoles by MAOS: a novel approach to cyclin-dependent kinase 5/p25 inhibitors as a potential treatment for Alzheimer's disease. 1729 69

Certain effects of melatonin on senescence were investigated. The experimental model used was 10-month-old senescence-accelerated mouse prone 8 (SAMP8). The mice in the experiment were administered melatonin (10 mg/kg) from the age of 1 month. Results showed that chronic administration of melatonin decreased cell loss in the cerebral cortex and reduced oxidative damage in protein and lipids. There are several studies suggesting that the activation of the cdk5/p35 pathway at its cleavage to cdk5/p25 may play a role in hyperphosphorylation of tau during aging and neurodegenerative diseases. Melatonin not only reduced the cerebral aging disturbances, but also prevented tau hyperphosphorylation present in the experimental model used in this study. Melatonin reduced cdk5 expression, as well as the cleavage of p35 to p25. The other tau kinase studied, GSK3beta, showed a reduction in this activity in comparison with SAMP8 nontreated SAMP8. These data indicate that melatonin possesses neuroprotective properties against cerebral damage gated to senescence. Moreover, these data suggest that the cdk5/GSKbeta signaling cascade has a potential role as a target for neurodegenerative diseases related to aging.
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PMID:Chronic administration of melatonin reduces cerebral injury biomarkers in SAMP8. 1743 56

Emergence of the cell cycle hypothesis in neurodegenerative disease comes from the numerous lines of evidence showing a tight link between "cell cycle-like reactivation" and neuronal death. Terminally differentiated neurons remain in G0 phase and display, compared to proliferating cells, an opposite regulation pattern of cell cycle markers in that most of the key activators and inhibitors are respectively down- and up-regulated. It has been clearly established that any experimental attempt to force terminally differentiated neurons to divide ultimately leads to their death. Conversely, cell cycle blockade in experimental models of neuronal death is able to rescue neurons. Hence, cell cycle deregulation is certainly among mechanisms governing neuronal death. However, many questions remain unresolved, especially those related to which molecular mechanisms trigger cell cycle deregulation and how this deregulation leads to cell death. In the present review, we focus on neurodegeneration in Alzheimer's disease and discuss the cell cycle deregulation related to this neurodegenerative pathology. Finally, we emphasize the role of p25/Cdk5 kinase complex in this pathological process through retinoblastoma protein phosphorylation and derepression of E2F-responsive genes and other actors such as cdc2, cyclins, and MCM proteins.
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PMID:The complex p25/Cdk5 kinase in neurofibrillary degeneration and neuronal death: the missing link to cell cycle. 1757 Dec 76

Based on the earlier results of our in-house database and compound library, a series of novel clubbed thienyl triazoles was designed which may emerge as potential cdk5/p25 inhibitors, for the treatment of Alzheimer's disease. A benign synthesis was planned so as to take an advantage of MAOS (Microwave Assisted Organic Synthesis) method. Evaluation of the SAR of this series has allowed the identification of compounds 4, 5, 7 and 8 from series I while 13, 14, 16 and 17 from series II as significant cdk5/p25 inhibitors and thus have potential as possible treatments for Alzheimer's disease.
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PMID:A novel approach to cyclin-dependent kinase 5/p25 inhibitors: A potential treatment for Alzheimer's disease. 1764 91

Hyperphosphorylated tau aggregates are the core constituent of neurofibrillary tangles. Recent research has shown a division between the presence of tangles, neurodegeneration and subsequent memory impairment, raising the possibility that an earlier pre-aggregated form of tau may be toxic. To gain further insight into the relationship between abnormal forms of tau, we have analyzed pathological changes in tau during tauopathy development in tangle-forming transgenic mice. In addition, we have quantified changes in the endogenous levels of a panel of protein kinases. We show progressive increases in aggregated tau and disease-specific conformational change, with hyperphosphorylation occurring in an age-dependent manner at specific sites. There were significant correlations between specific phosphorylation changes and amounts of aggregated tau and and abnormal tau conformations. Of the protein kinases tested, we found increases in phosphorylated (activated) p38 and the cyclin-dependent kinase-5 neuronal activators, p35 and p25, with aging, in the htau line, but not in non-tangle-forming control mice. Changes in tau kinases correlated with the amount of tau present in abnormal conformations and with insoluble tau in htau mice. These data suggest that cdk5 and p38 may be associated with pathological changes in wild-type human tau during the progressive development of tauopathy.
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PMID:Kinase activities increase during the development of tauopathy in htau mice. 1790 41


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