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

This study is to explore the effect of ginsenoside Rb1 on the process of beta-amyloid peptide(25-35) (Abeta(25-35)) -induced hyperphosphorylation of tau protein, and on the level of cyclin-dependent kinase 5 activator, p25/p35. Western blotting and/or immunocytochemical staining were used to detect the levels of phosphorylation of tau protein at the sites of Thr205, Ser396, Ser404 in hippocampal neurons, cdk5 and p25/p35. After exposure to Abeta(25-35) (20 micromol x L(-1)) for 12 h, the levels of tau protein phosphorylation at the sites of Thr205, Ser396, Ser404 were enhanced, the level of p25 was increased, but the level of protein cdk5 was not changed markedly. Pretreatment with ginsenoside Rb1 reduced Abeta(25-35) -induced hyperphosphorylation of tau protein and decreased the lever of p25, but had no effect on cdk5. Ginsenoside Rb1 can attenuate Abeta(25-35) -induced hyperphosphorylation of tau protein through CDK5 signal pathway.
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PMID:[Ginsenoside Rb1 attenuates beta-amyloid peptide(25-35) -induced hyperphosphorylation of tau protein through CDK5 signal pathway]. 1794 29

The mechanisms involved in neuronal loss in Parkinson's disease (PD) are not known, although recent studies performed in PD experimental models suggest that cdk5/p25 plays a predominant role. In the present study, we examined the gyrus cinguli of cases with PD and compared them with age-matched controls, and we demonstrated an activation of the calpain/cdk5 pathway. We found an increase in the p25/p35 immunoreactivity ratio and in the expression of transcription factor E2F-1. Our results implicate the cdk5/p25 pathway and re-entry into the cell cycle in the process of neuronal loss in patients with PD.
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PMID:Activation of the calpain/cdk5/p25 pathway in the girus cinguli in Parkinson's disease. 1797 53

The cyclin-dependent kinase cdk5 is atypically active in postmitotic neurons and enigmatic among the kinases proposed as molecular actors in neurodegeneration. We generated transgenic mice to express p25, the N-terminally truncated p35 activator of cdk5, in forebrain under tetracycline control (TET-off). Neuronal expression of p25 (p25(ON)) caused high mortality postnatally and early in life. Mortality was completely prevented by administration of doxycycline in the drinking water of pregnant dams and litters until P42, allowing us to study the action of p25 in adult mouse forebrain. Neuronal p25 triggered neurodegeneration and also microgliosis, rapidly and intensely in hippocampus and cortex. Progressive neurodegeneration was severe with marked neuron loss, causing brain atrophy (40% loss at age 5 months) with nearly complete elimination of the hippocampus. Neurodegeneration did not involve phosphorylation of protein tau or generation of amyloid peptide. Degenerating neurons did not stain for terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling or activated caspase-3 but were marked by FluoroJadeB in early stages. Diseased neurons were always closely associated with activated microglia already very early in the disease process. Primary neurons derived from p25 embryos were more prone to apoptosis than wild-type neurons, and they activated microglial cells in co-culture. The inducible p25 mice present as a model for neurodegeneration in hippocampal sclerosis and neocortical degeneration, with important contributions of activated microglia.
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PMID:Neurodegeneration and neuroinflammation in cdk5/p25-inducible mice: a model for hippocampal sclerosis and neocortical degeneration. 1820 85

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

Neuritic dystrophy with amyloid burden and neurofibrillary tangles are pathological hallmarks of Alzheimer's disease. Genetic disruption of CD40 or CD40L alleviates amyloid burden, astrocytosis, and microgliosis in transgenic animal models of Alzheimer's disease. It has been reported that phosphorylated tau-positive dystrophic neurites are observed in transgenic mice over-expressing human mutant beta-amyloid precursor protein (Tg2576). Here, we studied the pattern of phosphorylated tau (labeled with AT8, CP13, PG5, and PHF1 antibodies) and plaques using immunohistochemical techniques. Phosphorylated tau-positive dystrophic neurites were exclusively associated with Congo red-positive plaques as previously reported. Further, we show that CD40L or CD40 deficiency reduces the mean ratio of dystrophic neurite area to congophilic plaque area and the level of expression of cdk5 and p35/p25 in mice. In addition, we show that in a human neuroblastoma cell line treated with CD40L, cdk5 and p35/p25 are increased. Together, our data suggest that CD40-CD40L interaction has an effect on tau phosphorylation independent of beta-amyloid pathology, and that this effect may occur through a decrease of cdk5 and p35/p25.
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PMID:CD40 ligation mediates plaque-associated tau phosphorylation in beta-amyloid overproducing mice. 1860 55

Cdk5/p25 is a member of the family of cyclin-dependent, Ser/Thr kinases and is thought to play a causal role in Alzheimer's disease (AD) due to its ability to phosphorylate the protein tau, and thus promote the latter's aggregation into intraneuronal tangles. Given this, we and others are seeking inhibitors of cdk5/p25 as possible disease-modifying therapeutics for AD. In this paper, we first report the kinetic mechanism for the cdk5/p25-catalyzed phosphorylation of tau and histone H-1-derived peptide (H1P). These studies served as a necessary kinetic backdrop for investigations of the mechanism of inhibition by prototype inhibitors N4-(6-aminopyrimidin-4-yl)-sulfanilamide (APS) and 1-(5-cyclobutyl-thiazol-2-yl)-3-isoquinolin-5-yl-urea (CTIU). We found that the cdk5/p25-catalyzed phosphorylation of tau follows a rapid equilibrium, random kinetic mechanism, as evidenced by initial velocity analysis indicating sequential addition of tau and ATP, and studies of the mechanism of inhibition by substrate analogue AMP, product ADP, and analogues of peptide substrate H1P. Identical mechanistic conclusions were drawn when H1P was the phosphoryl acceptor. Subsequent studies of inhibition by APS and CTIU revealed that both compounds can bind to all four steady-state forms of the enzyme, to form the complexes E:I, E:I:tau, E:I:ATP, and E:I:tau:ATP. These results contrast with reported claims that APS and CTIU are competitive inhibitors of the binding of ATP.
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PMID:Kinetic studies of Cdk5/p25 kinase: phosphorylation of tau and complex inhibition by two prototype inhibitors. 1863 51

Hyperammonemia in neonates and infants causes irreversible damages in the developing CNS due to brain cell loss. Elucidating the mechanisms triggering ammonia-induced cell death in CNS is necessary for the development of neuroprotective strategies. We used reaggregated developing brain cell cultures derived from fetal rat telencephalon exposed to ammonia as an experimental model. Ammonia induced neuronal and oligodendroglial death, triggered apoptosis and activated caspases and calpain. Probably due to calpain activation, ammonia caused the cleavage of the cyclin-dependent kinase 5 activator, p35, to p25, the cdk5/p25 complex being known to lead to neurodegeneration. Roscovitine, a cdk5 inhibitor, protected neurons from ammonia-induced cell death. However, roscovitine also impaired axonal growth, probably through inhibition of the remaining cdk5/p35 activity, which is involved in neurite outgrowth. Thus, cdk5 appears as a promising therapeutic target for treating hyperammonemic newborns and infants, especially if one develops specific cdk5/p25 inhibitors.
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PMID:Role of caspases, calpain and cdk5 in ammonia-induced cell death in developing brain cells. 1872 28

p25/Cdk5 dysregulation may contribute to neurodegeneration. In this issue of Neuron, Kim et al. show that cdk5 inactivates HDAC-1, leading to cell cycle deregulation and DNA damage accumulation. This study provides further insights into the function of p25/Cdk5 in neurons and points to HDAC-1 as a target for therapeutic interventions.
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PMID:A sequel to the tale of p25/Cdk5 in neurodegeneration. 1908 76

Excess copper exposure is thought to be linked to the development of Alzheimer's disease (AD) neuropathology. However, the mechanism by which copper affects the CNS remains unclear. To investigate the effect of chronic copper exposure on both beta-amyloid and tau pathologies, we treated young triple transgenic (3xTg-AD) mice with 250 ppm copper-containing water for a period of 3 or 9 months. Copper exposure resulted in altered amyloid precursor protein processing; increased accumulation of the amyloid precursor protein and its proteolytic product, C99 fragment, along with increased generation of amyloid-beta peptides and oligomers. These changes were found to be mediated via up-regulation of BACE1 as significant increases in BACE1 levels and deposits were detected around plaques in mice following copper exposure. Furthermore, tau pathology within hippocampal neurons was exacerbated in copper-exposed 3xTg-AD group. Increased tau phosphorylation was closely correlated with aberrant cdk5/p25 activation, suggesting a role for this kinase in the development of copper-induced tau pathology. Taken together, our data suggest that chronic copper exposure accelerates not only amyloid pathology but also tau pathology in a mouse model of AD.
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PMID:Chronic copper exposure exacerbates both amyloid and tau pathology and selectively dysregulates cdk5 in a mouse model of AD. 1918 60

Increasing evidence implicates the c-Jun NH(2)-terminal kinase (JNK) pathway in the regulation of apoptosis in neurodegenerative diseases. In this study, we examined the neuroprotective effect of SP600125, a selective JNK inhibitor, in cerebellar granule cells (CGNs) deprived of serum and potassium (S/K withdrawal). S/K withdrawal-induced apoptosis occurs via activation of multiple pro-apoptotic pathways, including re-entry into the cell cycle, activation of glycogen synthase kinase-3 beta (GSK-3beta), cyclin-dependent kinase 5 (cdk5/p35) breakdown, formation of cdk5/p25 and JNK activation. Here we demonstrate that SP600125 is able to inhibit all these pro-apoptotic pathways via the inhibition of JNK. Further, we found that JNK inhibition maintains the phosphorylation/activation of Akt after S/K withdrawal. For further confirmation of this result, we studied several targets downstream of Akt including GSK-3beta, p-FOXO1, p-CREB and p35. In addition, the specific PI3K/Akt inhibitor LY294002 greatly diminished the antiapoptotic effects of SP600125 upon S/K withdrawal, confirming that Akt is involved in the neuroprotection achieved by SP600125. These results suggest that the maintenance of the PI3-kinase/Akt pathway by inhibition of JNK contributes to the prevention of apoptosis in rat cerebellar granule neurons mediated by S/K withdrawal. Furthermore, we propose that JNK may regulate the cell cycle re-entry by a novel mechanism that involves Akt, GSK-3beta and Rb phosphorylation.
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PMID:Neuroprotection by c-Jun NH2-terminal kinase inhibitor SP600125 against potassium deprivation-induced apoptosis involves the Akt pathway and inhibition of cell cycle reentry. 1935 94


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