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)

We have previously shown that N(6)-methyldeoxyadenosine (MDA) is an inducer of differentiation in several tumor cells. Here we show that in addition to its ability to induce neurite-outgrowth in PC12 cells, MDA also significantly enhances the nerve-growth factor-mediated neurite outgrowth of these cells. Thus, MDA acts synergistically with NGF to repress cdc2 and cdk2 synthesis and to enhance tyrosine hydroxylase synthesis. To further elucidate the mechanisms of action of MDA, we investigated the effect of this drug on various signaling pathways. The neuritogenesis observed in PC12 following MDA treatment is mediated through activation of adenylyl cyclase in a PKA independent process and through the recruitment of the p44/p42 MAPK pathway. Furthermore, the adenosine A(2a) receptor antagonist ZM 241385 prevents the MDA-induced neuritogenesis, suggesting that MDA mediates its effect via this adenylyl cyclase-coupled A(2a) receptor. Collectively, these findings suggest that, in PC12 cells, the MDA-induced neuritogenesis requires the recruitment of adenosine A(2a) receptor, the stimulation of adenylate cyclase, and the activation of the p44/42MAP kinase cascade.
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PMID:Induction of neurite outgrowth in PC12 cells by the bacterial nucleoside N6-methyldeoxyadenosine is mediated through adenosine A2a receptors and via cAMP and MAPK signaling pathways. 1272 27

Neuroadaptations induced by high-dose cocaine treatment have been hypothesized to persist after the cessation of drug treatment and mediate the expression of sensitization and tolerance to cocaine. We looked for evidence of these neuroadaptations in rats receiving more modest behaviorally effective cocaine treatments. Rats were exposed to either a sensitizing regimen of seven once-daily injections of 15 mg/kg cocaine or a tolerance-producing regimen involving a continuous infusion of the same daily dose. We assessed enzyme activity levels of protein kinase A and adenylate cyclase, and protein levels of tyrosine hydroxylase, cdk5 and neurofilaments in the nucleus accumbens and ventral tegmental area. Only protein kinase A activity levels were altered by cocaine treatment, but this alteration persisted for only 7 days, whereas a sensitized locomotor response was still evident at 21 days. Although behavioral tolerance to cocaine was seen the day after the termination of treatment, none of the molecular measures was altered on this or any other day. Thus, although increased protein kinase A activity can temporarily modulate sensitized responses to cocaine, alterations in total levels of the molecules assessed in our study do not correlate with the expression of sensitized or tolerant locomotor responses to cocaine.
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PMID:Neuroadaptations of total levels of adenylate cyclase, protein kinase A, tyrosine hydroxylase, cdk5 and neurofilaments in the nucleus accumbens and ventral tegmental area do not correlate with expression of sensitized or tolerant locomotor responses to cocaine. 1565 24

SH-SY5Y neuroblastoma cells, a model for studying neuronal differentiation, are able to differentiate into either cholinergic or dopaminergic/adrenergic phenotypes depending on media conditions. Using this system, we asked whether guanosine (Guo) or guanosine-5'-triphosphate (GTP) are able to drive differentiation towards one particular phenotype. Differentiation was determined by evaluating the frequency of cells bearing neurites and assessing neurite length after exposure to different concentrations of Guo or GTP for different durations. After 6 days, 0.3 mM Guo or GTP induced a significant increase in the number of cells bearing neurites and increased neurite length. Western blot analyses confirmed that purines induced differentiation; cells exposed to purines showed increases in the levels of GAP43, MAP2, and tyrosine hydroxylase. Proliferation assays and cytofluorimetric analyses indicated a significant anti-proliferative effect of purines, and a concentration-dependent accumulation of cells in S-phase, starting after 24 h of purine exposure and extending for up to 6 days. A transcriptional profile analysis using gene arrays showed that an up-regulation of cyclin E2/cdk2 evident after 24 h was responsible for S-phase entry, and a concurrent down-regulation of cell-cycle progression-promoting cyclin B1/B2 prevented S-phase exit. In addition, patch-clamp recordings revealed that 0.3 mM Guo or GTP, after 6 day incubation, significantly decreased Na(+) currents. In conclusion, we showed Guo- and GTP-induced cell-cycle arrest in neuroblastoma cells and suggest that this makes these cells more responsive to differentiation processes that favor the dopaminergic/adrenergic phenotype.
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PMID:Extracellular guanosine and GTP promote expression of differentiation markers and induce S-phase cell-cycle arrest in human SH-SY5Y neuroblastoma cells. 1911 4

Pharmacological dopamine replacement with l-3,4-dihydroxyphenylalanine (L-DOPA) remains the most effective approach to treat the motor symptoms of Parkinson's disease (PD). However, as the disease progresses, the therapeutic response to L-DOPA gradually becomes erratic and is associated with the emergence of dyskinesia in the majority of patients. The pathogenesis of L-DOPA-induced dyskinesia (LID) is still unknown. In the current study, using the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD, we demonstrated that the calcium-dependent proteins calpains and cdk5 of the striatum play a critical role in the behavioral and molecular changes evoked by L-DOPA therapy. We first confirmed that L-DOPA reversed PD symptoms, assessed by the cylinder, stepping and vibrissae-elicited reaching tests in this animal model, and elicited robust abnormal involuntary movements (AIMs) reminiscent of LID. Interestingly, intrastriatal infusion of the calpains inhibitor MDL28170, and to a lower extent the cdk5 inhibitor roscovitine, reduced the severity and amplitude of AIMs without affecting L-DOPA's antiparkinsonian effects. Notably, the calpains and cdk5 inhibitors totally reversed the striatal molecular changes attributed to L-DOPA therapy, such as ERK1/2 and dynamin phosphorylation. Another fascinating observation was that L-DOPA therapy, in combination with intrastriatal infusion of MDL28170, augmented tyrosine hydroxylase levels in the striatum of lesioned rats without affecting the number of dopaminergic cells in the substantia nigra. These findings disclose a novel mechanism underlying the maladaptive alterations induced by L-DOPA therapy in the 6-OHDA rat model of PD.
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PMID:Striatal inhibition of calpains prevents levodopa-induced neurochemical changes and abnormal involuntary movements in the hemiparkinsonian rat model. 2203 42