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 found in an active form only in neuronal cells. Activation by virtue of association with the cyclin-like neuronal proteins p35 (or its truncated form p25) and p39 is the only mechanism currently shown to regulate cdk5 catalytic activity. In addition to cyclin binding, other members of the cdk family require for maximal activation phosphorylation of a Ser/Thr residue (Thr(160) in the case of cdk-2) that is conserved in all cdks except cdk8. This site is phosphorylated by cdk-activating kinases, which, however, do not phosphorylate cdk5. To examine the possible existence of a phosphorylation-dependent regulatory mechanism in the case of cdk5, we have metabolically labeled PC12 cells with (32)P(i) and shown that the endogenous cdk5 is phosphorylated. Bacterially expressed cdk5 also can be phosphorylated by PC12 cell lysates. Phosphorylation of cdk5 by a PC12 cell lysate results in a significant increase in cdk5/p25 catalytic activity. Ser(159) in cdk5 is homologous to the regulatory Thr(160) in cdk2. A Ser(159)-to-Ala (S159A) cdk5 mutant did not show similar activation, which suggests that cdk5 is also regulated by phosphorylation at this site. Like other members of the cdk family, cdk5 catalytic activity is influenced by both p25 binding and phosphorylation. We show that the cdk5-activating kinase (cdk5AK) is distinct from the cdk-activating kinase (cyclin H/cdk7) that was reported previously to neither phosphorylate cdk5 nor affect its activity. We also show that casein kinase I, but not casein kinase II, can phosphorylate and activate cdk5 in vitro.
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PMID:Regulation of cyclin-dependent kinase 5 catalytic activity by phosphorylation. 1050 Jan 46

Cyclin-dependent kinase 5 (CDK5) is a unique CDK, the activity of which can be detected in postmitotic neurons. To date, CDK5 purified from mammalian brains has always been associated with a truncated form of the 35-kDa major brain specific activator (p35, also known as nck5a) of CDK5, known as p25. In this study, we report that p35 can be cleaved to p25 both in vitro and in vivo by calpain. In a rat brain extract, p35 was cleaved to p25 by incubation with Ca(2+). This cleavage was inhibited by a calpain inhibitor peptide derived from calpastatin and was ablated by separating the p35.CDK5 from calpain by centrifugation. The p35 recovered in the pellet after centrifugation could then be cleaved to p25 by purified calpain. Cleavage of p35 was also induced in primary cultured neurons by treatment with a Ca(2+) ionophore and Ca(2+) and inhibited by calpain inhibitor I. The cleavage changed the solubility of the CDK5 active complex from the particulate fraction to the soluble fraction but did not affect the histone H1 kinase activity. Increased cleavage was detected in cultured neurons undergoing cell death, suggesting a role of the cleavage in neuronal cell death.
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PMID:Calpain-dependent proteolytic cleavage of the p35 cyclin-dependent kinase 5 activator to p25. 1074 88

Cyclin-dependent kinase 5 is predominantly expressed in postmitotic neurons and plays a role in neurite elongation during development. It has also been postulated to play a role in apoptosis in a variety of cells, including neurons, but little is known about the generality and functional significance of cdk5 expression in neuronal apoptosis in living brain. We have therefore examined its expression and that of its known activators, p35, p39 and p67, in models of induced apoptosis in neurons of the substantia nigra. We find that cdk5 is expressed in apoptotic profiles following intrastriatal injection of 6-hydroxydopamine and axotomy. It is expressed exclusively in profiles which are in late morphologic stages of apoptosis. In these late stages, derivation of the profiles from neurons, and localization of expression to the nucleus, can be demonstrated by co-labeling with a neuron-specific nuclear marker, NeuN. In another model of induced apoptotic death in nigra, produced by developmental striatal lesion, kinase activity increases in parallel with cell death. While mRNAs for all three cdk5 activators are expressed in nigra during development, only p35 protein is expressed in apoptotic profiles. We conclude that cdk5/p35 expression is a general feature of apoptotic neuron death in substantia nigra neurons in vivo.
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PMID:Expression of cyclin-dependent kinase 5 and its activator p35 in models of induced apoptotic death in neurons of the substantia nigra in vivo. 1141 44

Cyclin-dependent kinase 5 (Cdk5), a cdc2-related kinase expressed in postmitotic neurons, is activated by association with a brain-specific activator, p35. It has been suggested that the conversion of p35 to p25 by the protease calpain is involved in neuronal cell death. However, p35 protein is turned over rapidly via proteasomal degradation in living neurons. In this study we show that the phosphorylation of p35 by Cdk5 suppresses the cleavage to p25 by calpain, whereas phosphorylation facilitates the proteasomal degradation of p35. The phosphorylation site in p35 that might be involved in preventing calpain cleavage was distinct from the phosphorylation site involved in facilitating proteasomal degradation. A phosphorylated form of p35 that was resistant to cleavage by calpain was more prevalent in the fetal brain, whereas the unphosphorylated form of p35 occurred in the adult brain. These results suggest that the phosphorylation of p35 serves as a protective mechanism that suppresses the generation of p25 in developing brains.
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PMID:Developmental regulation of the proteolysis of the p35 cyclin-dependent kinase 5 activator by phosphorylation. 1259 7

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

Cyclin-dependent kinase 5 (Cdk5) is a member of the cyclin-dependent kinase family and has been studied mainly in the differentiation of post-mitotic neurons. The purpose of this study was to determine the presence of cdk5 expression and activity in colon cancer cells and to investigate its role in the regulation of PPARgamma ligand-induced antiproliferation. We observed that cdk5 protein levels and kinase activity were elevated in both HT-29 cells and human tumor tissue in comparison to decreased levels in normal colonic mucosa. To elucidate cdk5's role in PPARgamma ligand-induced antiproliferation of colon cancer cells, HT-29 cells were treated with ciglitazone. A dose- and time-dependent decrease in cell proliferation were observed after ciglitazone exposure, which correlated with a decrease in cdk5 protein expression and kinase activity. Importantly, these ciglitazone-induced antiproliferative changes were reversed when cdk5 was overexpressed. Although present, p35, the regulatory protein of cdk5, showed no significant changes in protein expression with the introduction of ciglitazone. This is the first report of cdk5/p35 expression and kinase activity in colon cancer cells, which is associated with ciglitazone-induced antiproliferation in HT-29 cells.
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PMID:CDK5 is a novel regulatory protein in PPARgamma ligand-induced antiproliferation. 1632 95

Cyclin-dependent kinase 5 (CDK5), a unique member of the CDK family of cyclin-dependent kinases, is predominantly expressed in postmitotic neurons with proposed roles in both cell survival and programmed cell death. To understand how CDK5 participates in such disparate cellular outcomes, we investigated whether activation of CDK5 could mediate neuroprotection from serum deprivation by mu-opioid receptor agonist in differentiated SH-SY5Y cells and primary hippocampal neurons. We found that CDK5 kinase activity decreased following serum deprivation in differentiated SH-SY5Y cells coincident with increased cell loss and activation of caspases cascade activation, which was reversed by opioid antagonist. Overexpression of CDK5 in serum-free medium reversed activation of caspase cascade and augmented DAMGO neuroprotection. Blocking CDK5 activity by pharmacologic inhibitor, roscovitine or overexpression of dominant negative CDK5 augmented activation of cell death markers and diminished mu-opioid receptor agonist protection. Reduction in CDK5 activity corresponded to reduction in protein levels of CDK5 activator p35 during serum deprivation which was also reversed by mu-opioid receptor agonist. Phosphorylation of STAT3 at Serine 727 by CDK5 decreased during serum deprivation, and partly recovered by mu-opioid agonist. PI3K signaling pathway was not required for CDK5-mediated mu-opioid neuroprotection against serum deprivation. These findings indicate that neuroprotection by mu-opioid receptor agonist against serum deprivation is mediated by activation of CDK5 through up-regulation of p35 and phosphorylation of STAT3 by CDK5 may contribute to the neuroprotection.
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PMID:Role of CDK5 in neuroprotection from serum deprivation by mu-opioid receptor agonist. 1687 21

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

Cyclin-dependent kinase 5 (CDK-5) appears to play a significant role in peripheral nerve regeneration as CDK-5 inhibition retards nerve regeneration following nerve crush. Anti-inflammatory drug acetyl salicylic acid elevates CDK-5 and reduces ischemia - reperfusion injury in cultured neurons. In this study we have evaluated the effect of acetyl salicylic acid on functional recovery following sciatic nerve crush in mice. Eighteen Swiss albino mice underwent unilateral sciatic nerve crush. Test animals received acetyl salicylic acid (100 mg/kg/day, n = 6 or 50 mg/kg/day, n = 6) and control animals (n = 6) received normal saline for 14 days following surgery. Functional recovery was assessed with improvement in Sciatic Function Index, nociception and gait. In comparison with normal saline treatment, acetyl salicylic acid (100 mg/kg/day) significantly improved functional recovery following sciatic nerve crush. Anti-inflammatory drug acetyl salicylic acid appears to be a promising agent for treating peripheral nerve injuries and hence elucidation of its neuroprotective pathways is necessary.
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PMID:Acetyl salicylic acid augments functional recovery following sciatic nerve crush in mice. 1727 29

Cyclin-dependent kinase 5 (CDK-5) is reported to phosphorylate the NMDA receptor prior to the induction of long-term potentiation (LTP), among its many other effects. Application of CDK-5 inhibitors disrupts LTP and results in impaired task acquisition in behaving animals. In this study, we investigated the effect of exogenously applied roscovitine, a potent CDK-5 inhibitor, on consolidation and reconsolidation processes in day-old male chicks. New Hampshire x White leghorn cockerels were trained using a modified version of the passive avoidance learning task. Intracranial injections of roscovitine (2.5 microM) administered immediately after training induced a memory deficit that evolved from 5-minute post-training and persisted until at least 24 h following training. Injections of roscovitine (2.75 microM) administered immediately after the reminder trial induced a memory deficit observed by 30-minute post-reminder which had resolved by 24 h following the reminder. The comparison between consolidation and reconsolidation demonstrates differences both in the time of the onset of the memory deficit as well as in the permanence of this deficit. The results suggest an important, although different role for CDK-5 in consolidation and reconsolidation processes following passive avoidance learning.
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PMID:Inhibition of cyclin-dependent kinase 5 by roscovitine impairs memory consolidation and reconsolidation in the day-old chick. 1862 76


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