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)

Previous evidence from our lab and others has implicated the mitotic cdc2/cyclin B1 kinase in the neurofibrillary degeneration of Alzheimer's disease. To examine the specificity of this relationship, and define conditions leading to atypical activation of mitotic kinase in postmitotic neurons, we have applied antibodies specific for the cdc2 kinase, its activator, cyclin B1, and three cdc2 produced phosphoepitopes: the TG-3 phosphoepitope in tau and nucleolin, the MPM-2 phosphoepitope in a variety of substrates, and the H5 phosphoepitope in RNA polymerase II, to affected brain regions from a spectrum of neurodegenerative disorders. Our results demonstrate that neurons containing characteristic lesions in a subset of diseases including Down Syndrome (DS), Frontotemporal Dementia linked to chromosome 17 (FTD-17), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Parkinson-Amyotrophic Lateral Sclerosis of Guam (GP-ALS), Niemann Pick disease type C (NPDC), and Pick's disease, display mitotic indices, implicating diverse etiologies in mitotic activation. The convergence of various degenerative schemes into a unified mitotic kinase-driven pathway provides a common target for therapeutic treatment of these different disorders.
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PMID:Mitotic activation: a convergent mechanism for a cohort of neurodegenerative diseases. 1112 25

Recent research points to an involvement of deregulated cdk5 activity in the pathogenesis of mutant SOD1-mediated disease. In addition, inhibition of this activity might promote motor neuron survival. These observations have opened the door to further research into the role of cdk5 in ALS and other neurodegenerative diseases.
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PMID:Cdk5 sinks into ALS. 1180 24

The discovery of cell cycle regulators has directed cell research into uncharted territory. In dividing cells, cell cycle-associated protein kinases, which are referred to as cyclin-dependent-kinases (Cdks), regulate proliferation, differentiation, senescence and apoptosis. In contrast, all Cdks in post-mitotic neurons, with the notable exception of Cdk5, are silenced. Surprisingly, misregulation of Cdks occurs in neurons in a wide diversity of neurological disorders, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Ectopic expression of these proteins in neurons potently induces cell death with hallmarks of apoptosis. Deregulation of the unique, cell cycle-unrelated Cdk5 by its truncated co-activator, p25 and p29, contributes to neurodegeneration by altering the phosphorylation state of non-membrane-associated proteins and possibly through the induction of cell cycle proteins. On the other hand, cycling Cdks such as Cdk2, Cdk4 and Cdk6, initiate death pathways by derepressing E2F-1/Rb-dependent transcription at the neuronal G1/S checkpoint. Thus, Cdk5 and cycling Cdks may have little in common in the healthy CNS, but they likely conspire in leading neurons to their demise.
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PMID:Cycling at the interface between neurodevelopment and neurodegeneration. 1247 66

Cdk5, a member of the cyclin-dependent kinase (cdk) family, is predominantly active in neurons, where its activity is tightly regulated by the binding of its neuronal activators p35 and p39. Cdk5 is implicated in regulating the proper neuronal function; a deregulation of cdk5 has been found associated with Alzheimer's disease and amyotrophic lateral sclerosis. As oxidative stress products have been seen co-localized with pathological hallmarks of neurodegenerative diseases, we studied the effect of oxidative stress on the cdk5 enzyme in human neuroblastoma IMR-32 cells. We evaluated the effects of 4-hydroxynonenal and Ascorbate plus FeSO(4) on cdk5 activity and on the expression of cdk5 and p35 proteins. We report here that oxidative stress stimulates cdk5 activity and induces an upregulation of its regulatory and catalytic subunit expression in IMR-32 vital cells, showing that the cdk5 enzyme is involved in the signaling pathway activated by oxidative stress.
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PMID:Up-regulation of cDK5/p35 by oxidative stress in human neuroblastoma IMR-32 cells. 1257 9

There is growing evidence for involvement of members of the cyclin-dependent kinase (Cdk) family in neurodegenerative disorders and in apoptotic death of neurons subjected to various insults. After our recent report that a deregulation of Cdk5 activity by p25 may contribute to pathogenesis of amyotrophic lateral sclerosis (ALS), we further examined the possible involvement of other Cdks in mice expressing a mutant form of superoxide dismutase (SOD1(G37R)) linked to ALS. No substantial changes in Cdk2 or Cdk6 distribution and kinase activities were detected in spinal motor neurons from SOD1(G37R) mice when compared with normal mice. Of particular interest was the upregulation and mislocalization of Cdk4, a regulator of the G1-S checkpoint of the cell cycle, in motor neurons of SOD1(G37R) mice. The increase of Cdk4 activity in SOD1(G37R) mice was associated with an increase in nuclear Cdk4, cyclin D1, its coactivator, and with the abnormal phosphorylation of the retinoblastoma (Rb) protein at Cdk phosphorylation sites. Pharmacological treatment of SOD1(G37R) mice with minocycline, a compound that attenuates microgliosis and slows down disease, lessened the dysregulation of Cdk5/Cdk4 and the phosphorylation of Rb. Interestingly, phospho-Rb was immunoprecipitated with anti-Cdk4 but not with anti-Cdk5 antibodies, suggesting a key role for Cdk4 in the phosphorylation of Rb. Remarkably, the overexpression of a transgene coding for human neurofilament H, a phosphorylation sink for deregulated Cdk5 activity by p25, resulted in a reduction in levels of nuclear Cdk4 and Rb phosphorylation. These results indicate that a cell cycle signaling at the neuronal G1-S checkpoint subsequent to Cdk5 deregulation may constitute a critical step of the neuronal death pathway in ALS caused by mutant SOD1.
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PMID:Cell cycle regulators in the neuronal death pathway of amyotrophic lateral sclerosis caused by mutant superoxide dismutase 1. 1265 72

Cyclin-dependent kinase 5 (CDK5) plays an essential role in the development of the central nervous system during mammalian embryogenesis. In the adult, CDK5 is required for the maintenance of neuronal architecture. Its deregulation has profound cytotoxic effects and has been implicated in the development of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. In this review, we concentrate on the regulation of CDK5 activity, privileging a structural perspective based on a decade of structural analyses of different members of the CDK family, including CDK2 and CDK5. We review the activation mechanism of CDK5 and discuss its differences and similarities with that of CDK2 and of the other members of the CDK family.
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PMID:The structural perspective on CDK5. 1467 2

Dysregulation of cyclin-dependent kinases (cdks) and cytoskeletal protein hyperphosphorylation characterizes a subset of human neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, and Niemann-Pick Type C (NPC). It is thought that these cytoskeletal changes lead eventually to development of hallmark cytoskeletal lesions such as neurofibrillary tangles and axonal spheroids. Although many studies support an involvement of cdks in these neurodegenerative cascades, it is not known whether cdk activity is essential. The naturally occurring npc-1 mutant mouse mimics human NPC, in displaying activation of cdk5, mitotic cdc2, and cdk4, with concomitant cytoskeletal pathology and neurodegeneration. We availed of this model and specific pharmacological inhibitors of cdk activity, to determine whether cdks are necessary for NPC neuropathology. The inhibitors were infused intracerebroventricularly for a 2-week period, initiated at a pathologically incipient stage. While an inactive stereoisomer, iso-olomoucine, was ineffective, two potent inhibitors, roscovitine and olomoucine, attenuated significantly the hyperphosphorylation of neurofilament, tau, and mitotic proteins, reduced the number of spheroids, modulated Purkinje neuron death, and ameliorated motor defects in npc mice. These results suggest that cdk activity is required for neuropathology and subsequent motor impairment in NPC. Studies aimed at knocking down individual cdks in these mice will help identify the specific cdk(s) that are essential, and delineate their precise roles in the neurodegenerative process.
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PMID:Cyclin-dependent kinase inhibitors attenuate protein hyperphosphorylation, cytoskeletal lesion formation, and motor defects in Niemann-Pick Type C mice. 1533 9

DNA damage and activation of the cell cycle have been implicated in numerous neurodegenerative diseases, including Alzheimer disease, Parkinson's disease, and amyotrophic lateral sclerosis. To better understand the role of cell cycle proteins in DNA-damage induced neuronal cell death, we examined various cell cycle proteins during camptothecin-induced death of human neuroblastoma cells. We report a rapid induction of p53 and increased expression of p21, concurrent with reduced levels of many cell cycle proteins that regulate G1 to S phase cell cycle progression. However, we found increased levels of cdk2 and cyclin E, and formation of a cyclin E-cdk2-p21 protein complex. DNA damage failed to induce activation and progression of the cell cycle. Finally, camptothecin-induced neuronal cell death occurred concurrent with phosphorylation of histone H2B. Pretreatment of cells with cdk inhibitor olomoucine impeded cdk2-cyclin E accumulation, but not the induction of p53. Olomucine concurrently delayed histone H2B phosphorylation, caspase-3 activation and cell death. These findings suggest that DNA-damage of differentiated neuroblastoma cells induces a rapid p53-mediated inhibition of cell cycle progression and induction of cdk2-cyclin E, followed by caspase-3 activation, phosphorylation of histone and cell death.
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PMID:DNA damage induces cdk2 protein levels and histone H2B phosphorylation in SH-SY5Y neuroblastoma cells. 1615 45

The proline-directed serine threonine kinase, Cdk5, is an unusual molecule that belongs to the well-known large family of proteins, cyclin-dependent kinases (Cdks). While it has significant homology with the mammalian Cdk2 and yeast cdc2, unlike the other Cdks, it has little role to play in cell cycle regulation and is activated by non-cyclin proteins, p35 and p39. It phosphorylates a spectrum of proteins, most of them associated with cell morphology and motility. A majority of known substrates of Cdk5 are cytoskeletal elements, signalling molecules or regulatory proteins. It also appears to be an important player in cell-cell communication. Highly conserved, Cdk5 is most abundant in the nervous system and is of special interest to neuroscientists as it appears to be indispensable for normal neural development and function. In normal cells, transcription and activity of Cdk5 is tightly regulated. Present essentially in post-mitotic neurons, its normal activity is obligatory for migration and differentiation of neurons in developing brain. Deregulation of Cdk5 has been implicated in Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease and acute neuronal injury. Regulators of Cdk5 activity are considered as potential therapeutic molecules for degenerative diseases. This review focuses on the role of Cdk5 in neural cells as regulator of cytoskeletal elements, axonal guidance, membrane transport, synaptogenesis and cell survival in normal and pathological conditions.
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PMID:An unusual member of the Cdk family: Cdk5. 1818 83

The deposition of highly phosphorylated microtubule-associated tau protein has been observed in ALS with cognitive impairment (ALSci). In these studies, we have examined whether the expression of two candidate protein kinases for mediating tau hyperphosphorylation (GSK3beta or CDK5) are also altered. The expression of GSK, CDK and p25/p35 was assayed in human frontal, hippocampal, cerebellar, cervical (dorsal and ventral) and lumbar (dorsal and ventral) tissue from neurologically intact control (5), ALS (5) or ALSci (5) patients using RT-PCR, Western blot or immunohistochemistry. To assess GSK-3beta activity, we examined GSK3beta, phospho-GSK3beta and phospho-beta-catenin expression. Expression levels relative to that of beta-actin were compared by ANOVA. The expression of GSK, GSK3beta and phospho-GSK3beta was increased in both ALS and ALSci compared to that of the control. This was accompanied by an increased expression of phospho-beta-catenin. No significant difference between control, ALS or ALSci was observed with respect to the expression of CDK5 or p25/p35. Both GSK3beta and phospho-GSK3beta immunoreactive neurons were mainly located in layer II and layer III in the frontal cortex and in layer II in the hippocampus. This was consistent with the previously described distribution of hyperphosphorylated tau bearing neurons in ALS and ALSci. These data suggest that GSK3beta expression is upregulated in ALS and ALSci and that GSK3beta activation is associated with the intraneuronal deposition of hyperphosphorylated tau protein. This supports the potential role for GSK3beta as a therapeutic target in ALS.
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PMID:Upregulation of GSK3beta expression in frontal and temporal cortex in ALS with cognitive impairment (ALSci). 1822 34


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