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)

Lithium can interfere with embryonal development in a variety of organisms. We investigated the effect of lithium on the proliferation of early embryonal cells. [3H]Thymidine incorporation of non-committed mouse P19 embryonal carcinoma cells was inhibited by lithium treatment. Similar effects were seen in a variety of other cells. This growth inhibition occurred in the G2 phase, since cells accumulated with a 4N DNA content, but the appearance of mitotic cells was blocked. Lithium could also prevent the activation of cdc2, thereby inhibiting cyclin B/cdc2 kinase activity. These data indicate that lithium might disturb embryonal development through interference in embryonal cell cycle regulation.
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PMID:Inhibition of cell proliferation by lithium is associated with interference in cdc2 activation. 1048 56

Lithium, a therapeutic agent for bipolar disorder, can induce G2/M arrest in various cells, but the mechanism is unclear. In this article, we demonstrated that lithium arrested hepatocellular carcinoma cell SMMC-7721 at G2/M checkpoint by inducing the phosphorylation of cdc2 (Tyr-15). This effect was p53 independent and not concerned with the inhibition of glycogen synthase kinase-3 and inositol monophosphatase, two well-documented targets of lithium. Checkpoint kinase 1 (Chk1), a critical enzyme in DNA damage-induced G2/M arrest, was at least partially responsible for the lithium action. The lithium-induced phosphorylation of cdc2 and G2/M arrest was abrogated largely by SB218078, a potent Chk1 inhibitor, as well as by Chk1 siRNA or the over-expression of kinase dead Chk1. Furthermore, lithium-induced cdc25C phosphorylation in 7721 cells and in vitro kinase assay showed that the activity of Chk1 was enhanced after lithium treatment. Interestingly, the increase of Chk1 activity by lithium may be independent of ataxia telangiectasia mutated (ATM)/ATM and Rad3-related (ATR) kinase. This is because no elevated phosphorylation on Chk1 (Ser-317 and Ser-345) was observed after lithium treatment. Moreover, caffeine, a known ATM/ATR kinase inhibitor, relieved the phosphorylation of cdc2 (Tyr-15) by hydroxyurea, but not that by lithium. Our study's results revealed the role of Chk1 in lithium-induced G2/M arrest. Given that Chk1 has been proposed to be a novel tumor suppressor, we suggest that the effect of lithium on Chk1 and cell cycle is useful in tumor prevention and therapy.
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PMID:Involvement of the role of Chk1 in lithium-induced G2/M phase cell cycle arrest in hepatocellular carcinoma cells. 1824 28

Lithium reduced striatal neurodegeneration induced in rats by 3-nitropropionic acid inhibiting calpain activation. Lithium prevented an increase in cdk5 activity, as shown by the levels of the co-activator p35. Myocite enhancer factor 2 (MEF2), a downstream substrate for cdk5 with pro-survival activity, showed increased phosphorylation. In primary cultures of neurons treated with 3-NP, lithium also reduced protease activity mediated by calpain, cdk5 activation and cellular death. These observations indicate that lithium has a neuroprotective effect. Lithium treatment also reduced the intracellular increase in calcium induced by 3-NP. The finding that lithium mediates the modulation of the calpain/cdk5 pathway further supports its use in the treatment of neurodegenerative diseases.
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PMID:Evidence of calpain/cdk5 pathway inhibition by lithium in 3-nitropropionic acid toxicity in vivo and in vitro. 1894 25

Lithium is a simple cation that has been used clinically since 1950 for the treatment of bipolar disorder. However in the last decade numerous studies either using animal models or human trials suggest that this cation may delay progression of neurodegenerative diseases. One of the main challenges facing researchers in the neurosciences is to identify key molecules in neuronal apoptosis. This would facilitate the identification of targets in order to design drugs for the treatment of Alzheimer's disease, Parkinson's disease and other neurological disorders. Although enormous effort has been made in the past few years and it has been demonstrated that the mitochondria comprise a key component of the neuronal apoptotic route, it seems that in addition to the mitochondria other intracellular components are implicated in this process. It has been proposed that DNA damage and re-entry into the cell cycle or the activation of different proteases, such as calpain, could constitute a common pathway in the apoptotic process and thus death processes in neurological diseases. The hypothesis about the implication of calpain in neuronal cell death is supported by existing data on neurodegenerative disorders in the brains of patients who show an increase in proteolytic activity of calpain compared with control brains. Indeed, studies performed in neuronal cell preparations suggest that activation of this protease is accompanied by other features such as structural modifications of the cytoskeleton, cleavage of several receptors, activation of kinases, such as cdk5 or GSK3ss, etc. Here, we summarize the potential routes involved in neurodegenerative disorders related to calpain activation, mainly those connected with changes in calcium homeostasis machinery, activation of kinase pathways, transcription factors, and the cell cycle.
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PMID:Calpains as a target for therapy of neurodegenerative diseases: putative role of lithium. 1968 41