Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have demonstrated that multiple agents that promote survival of PC12 cells and sympathetic neurons deprived of trophic support also block cell cycle progression. Presently, we address whether inhibition of cell cycle-related cyclin-dependent kinases (CDKs) prevents neuronal cell death. We show that two distinct CDK inhibitors, flavopiridol and olomoucine, suppress the death of neuronal PC12 cells and sympathetic neurons. In addition, we demonstrate that inhibitor concentrations required to promote survival correlate with their ability to inhibit proliferation. Promotion of survival, however, does not correlate with inhibition of extracellular signal-regulated kinase or c-Jun kinase activities or with interference with the activation of c-Jun kinase that accompanies serum/nerve growth factor deprivation. In contrast to their actions on nerve growth factor-differentiated PC12 cells, the CDK inhibitors do not prevent the death of proliferation-competent PC12 cells and, in fact, promote their cell death. These findings support the hypothesis that post-mitotic neuronal cells die after removal of trophic support due to an attempt to re-enter the cell cycle in an uncoordinated and inappropriate manner. We speculate that cycling PC12 cells are not saved by these agents due to a signaling conflict between an inherent oncogenic signal and the inhibition of CDK activity.
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PMID:Inhibitors of cyclin-dependent kinases promote survival of post-mitotic neuronally differentiated PC12 cells and sympathetic neurons. 862 6

Cyclin-dependent kinases and mitogen-activated protein kinases have been implicated in the regulation of cellular survival and apoptosis. We tested the effect of two mitogen-activated/cyclin-dependent kinase inhibitors, olomoucine and butyrolactone I, on the in vitro survival of chick embryonic neurons. Sensory, sympathetic, and ciliary neurons, when prepared at their respective time point of programmed cell death, could be rescued from apoptosis by both inhibitors in a dose-dependent fashion. In contrast, dividing sympathetic precursors underwent apoptosis when treated with olomoucine, but not butyrolactone I, at the same range of concentration. With similar potency, olomoucine and butyrolactone I inhibited immunocomplex c-Jun kinase activity. Both substances inhibited neurite outgrowth in a dose-dependent manner; developmentally younger neurons were more sensitive to this effect than older ones. These results suggest that certain mitogen-activated/cyclin-dependent kinases associated with cell division in neuronal precursors (i) may become essential components of the apoptotic machinery by the time neurons reach their phase of naturally occurring cell death and (ii) may be necessary for neurite outgrowth during development.
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PMID:Survival-promoting activity of inhibitors of cyclin-dependent kinases on primary neurons correlates with inhibition of c-Jun kinase-1. 933 2

Intrinsic expression of the multidrug resistance (MDR) transporter P-glycoprotein (Pgp) may be regulated by reactive oxygen species (ROS). A transient expression of Pgp was observed during the growth of multicellular tumor spheroids. Maximum Pgp expression occurred in tumor spheroids with a high percentage of quiescent, Ki-67-negative cells, elevated glutathione levels, increased expression of the cyclin-dependent kinase inhibitors p27Kip1 and p21WAF-1 as well as reduced ROS levels and minor activity of the mitogen-activated kinase (MAPK) members c-Jun amino-terminal kinase (JNK), extracellular signal-regulated kinase ERK1,2, and p38 MAPK. Raising intracellular ROS by depletion of glutathione with buthionine sulfoximine (BSO) or glutamine starvation resulted in down-regulation of Pgp and p27Kip1, whereas ERK1,2 and JNK were activated. Down-regulation of Pgp was furthermore observed with low concentrations of hydrogen peroxide and epidermal growth factor, indicating that ROS may regulate Pgp expression. The down-regulation of Pgp following BSO treatment was abolished by agents interfering with receptor tyrosine kinase signaling pathways, i.e. the protein kinase C inhibitors bisindolylmaleimide I (BIM-1) and Ro-31-8220, the p21ras farnesyl protein transferase inhibitor III, the c-Raf inhibitor ZM 336372 and PD98059, which inhibits ERK1,2 activation. ROS involved as second messengers in receptor tyrosine kinase signaling pathways may act as negative regulators of Pgp expression.
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PMID:Down-regulation of intrinsic P-glycoprotein expression in multicellular prostate tumor spheroids by reactive oxygen species. 1127 18

In response to DNA damage, p53 protein transiently stabilizes and accumulates in the nucleus, where it performs its role as a transcription factor. Phosphorylation of p53 increases its sequence-specific DNA-binding activity. In the present study, we have examined the effect of methylmethane sulfonate (MMS) to HCT-116 human colon cancer cells on the phosphorylation of p53. Results show that p53 protein becomes phosphorylated at serine 15 (Ser15) and Ser392 residues after treatment with MMS in a time-dependent manner. Increased levels of phospho-p53(Ser15) and phospho-p53(Ser392) were maintained up to 50 h of the MMS treatment. We also examined the involvement of probable kinase(s), which could be responsible for MMS-induced phosphorylation of p53 at Ser15 and Ser392. In vitro phosphorylation assay, carried out with the immunoprecipates of MMS-treated cells, showed an increased phosphorylation of p53 by c-Jun kinase 1 (JNK1) at early time points (2.5 h). However, with cyclin-dependent kinase (Cdk2) and TFIIH complex associated kinase CAK, the phosphorylation of p53 was increased at later time points (25 h). The phosphorylation of p53 by Cdc2 and MAPK (p38) kinases remained unaffected in the MMS-treated versus untreated cells. The MMS-induced phosphorylation of p53 correlates with our previous findings of p53's ability for increased sequence-specific DNA-binding and transcriptional activity in the cells treated with DNA alkylating agents.
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PMID:DNA alkylation-induced phosphorylation of p53 and activation of kinases in colon cancer cells. 1149 44

DNA damage, an important initiator of neuronal death, has been implicated in numerous neurodegenerative conditions. We previously delineated several pathways that control embryonic cortical neuronal death evoked by the DNA-damaging agent, camptothecin. In this model, the tumor suppressor p53 and cyclin-dependent kinases (CDKs) are activated independently and cooperate to mediate the conserved death pathway. To further our understanding, we presently examined whether the c-Jun/JNK pathway modulates death and whether this pathway is regulated by CDKs, p53, and Bax. We show that c-Jun/JNK is activated following DNA damage. Moreover, the c-Jun pathway is one mediator of death, because expression of dominant negative c-Jun and cdc42, and JNK pathway inhibitors are neuroprotective. Although previous evidences indicate that JNK3 is required for neuronal death under certain conditions, we show that JNK3 deficiency only partially mediates c-Jun phosphorylation and its deficiency does not protect neurons from death. Interestingly, we provide evidence that CDK activity regulates c-Jun but does not affect upstream pathways that lead to JNK phosphorylation. Finally, c-Jun activation is independent of p53 and Bax. Accordingly, we propose that c-Jun is regulated by the JNK and CDK pathways and that both must be activated for efficient c-Jun activation to occur.
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PMID:Interaction of the c-Jun/JNK pathway and cyclin-dependent kinases in death of embryonic cortical neurons evoked by DNA damage. 1209 88

The cyclin-dependent kinase (cdk) inhibitor p27(Kip1) is a central mediator in the imposition and maintenance of quiescence through the sequestration of G(1)-specific cyclin-cdk complexes. Previous studies have implicated the c-Jun co-activator protein Jab1 as a regulator of intracellular p27(Kip1) levels. Jab1 has been reported to interact with p27(Kip1) and cause its translocation to the cytoplasm as a prelude to the degradation of the cdk inhibitor. Here we describe experiments that showing phosphorylation of p27(Kip1) at serine 10 leads to the suppression of Jab1 levels with the concomitant inhibition of c-Jun-dependent transcription. This repression is minimized upon quiescence exit through the rapid and preferential loss of the serine 10-phosphorylated form of p27(Kip1) following serum stimulation. Our results, therefore, demonstrate an additional role for p27(Kip1) in the modulation of c-Jun-dependent transcription via Jab1.
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PMID:Jab1 co-activation of c-Jun is abrogated by the serine 10-phosphorylated form of p27Kip1. 1211 82

We have assessed the growth response of Chinese-hamster ovary (CHO) cells to activation of recombinantly expressed G-protein-coupled muscarinic M(2) or M(3) acetylcholine receptors (AChRs). We show that activation of these receptors leads to divergent growth responses: M(2) AChR activation causes an increase in DNA synthesis, whereas M(3) AChR activation causes a dramatic decrease in DNA synthesis. We have characterized the M(3) AChR-mediated growth inhibition and show that it involves a G(1) phase cell-cycle arrest. Further analysis of this arrest indicates that it involves an increase in expression of the cyclin-dependent kinase (CDK) inhibitor, p21(Cip1/Waf1) (where Cip1 is CDK-interacting protein 1 and Waf1 is wild-type p53-associated fragment 1), in response to M(3) AChR activation. This increase in protein expression leads to an increase in p21(Cip1/Waf1) association with CDK2, a decrease in CDK2 activity and an accumulation of hypophosphorylated retinoblastoma protein. The increased p21(Cip1/Waf1) expression is due, at least in part, to an increase in p21(Cip1/Waf1) mRNA, and receptor-mediated changes in phosphorylation of c-Jun provide a mechanism to account for this p21(Cip1/Waf1) transcriptional regulation. Evaluation of the extracellular signal-regulated protein kinase and c-Jun N-terminal kinase activities has shown striking differences in the profiles of activation of these mitogen-activated protein kinases by the M(2) and M(3) AChRs, and their potential involvement in mediating growth arrest by the M(3) AChR is discussed.
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PMID:Growth inhibition by the muscarinic M(3) acetylcholine receptor: evidence for p21(Cip1/Waf1) involvement in G(1) arrest. 1212 81

Activation of the JNK pathway and induction of the AP-1 transcription factor c-Jun are critical for neuronal apoptosis caused by a variety of insults. Ara-C-induced DNA damage caused rapid sympathetic neuronal death that was associated with an increase of c-jun expression. In addition, c-Jun was phosphorylated in its N-terminal transactivation domain, which is important for c-Jun-mediated gene transcription. Blocking c-Jun activation by JNK pathway inhibition prevented neuronal death after stress. In contrast, neither the JNK inhibitor SP600125 nor the mixed lineage kinase inhibitor CEP-1347 prevented cytosine arabinoside-induced neuronal death, demonstrating that the JNK pathway was not necessary for DNA damage-induced neuronal apoptosis. Surprisingly, SP600125 or CEP-1347 could not block c-Jun induction or phosphorylation after DNA damage. Pharmacological inhibitors of cyclin-dependent kinase (CDK) activity completely prevented c-Jun phosphorylation after DNA damage. These results demonstrate that c-Jun activation during DNA damage-induced neuronal apoptosis was independent of the classical JNK pathway and was mediated by a novel c-Jun kinase. Based on pharmacological criteria, DNA damage-induced neuronal c-Jun kinase may be a member of the CDK family or be activated by a CDK-like kinase. Activation of this novel kinase and subsequent phosphorylation of c-Jun may be important in neuronal death after DNA damage.
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PMID:JNK-independent activation of c-Jun during neuronal apoptosis induced by multiple DNA-damaging agents. 1268 20

In the lactating mammary gland, weaning produces mitochondrial cytochrome c release and nuclear DNA fragmentation, as determined by gel electrophoresis. This is followed by a significant decrease in lactation. Weaning for 2 h produces an early induction of the tumour suppressor/transcription factor p53, whereas the oncoprotein c-Jun and c-Jun N-terminal kinase are elevated after 24 h of weaning when compared with controls. The expression of p21(cip1) and p27(kip1), cyclin-dependent kinase inhibitors, was significantly higher in weaned rats when compared with control lactating rats. All the changes mentioned above also happen in the lactating mammary gland when propargylglycine, an inhibitor of the liver trans-sulphuration pathway, is administered. This effect is partially reversed by N -acetylcysteine administration. The administration of buthionine sulphoximine, an irreversible inhibitor of gamma-glutamylcysteine synthetase, to lactating rats produces a decrease in GSH levels and changes in protein concentrations and gene transcripts similar to those in rats with impaired trans-sulphuration pathway. These data suggest that the inter-tissue flux of GSH is an important mechanism of L-cysteine delivery to the lactating mammary gland and emphasize the importance of this physiological event in maintaining the gene expression required to sustain lactation.
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PMID:Inhibition of liver trans-sulphuration pathway by propargylglycine mimics gene expression changes found in the mammary gland of weaned lactating rats: role of glutathione. 1272 69

Chronic ethanol consumption can result in hepatic fibrosis and cirrhosis. In addition to oxidative metabolism, ethanol can be metabolized by esterification with fatty acids to form fatty acid ethyl esters (FAEE) such as linolenic acid ethyl ester (LAEE). We have previously demonstrated that LAEE has promitogeinc and activating effects on hepatic stellate cells (HSC), but the mechanisms of these actions are not known. Intracellular signaling through MAP kinase pathways, including extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) can influence the activity of the transcription factor AP-1, while cell-cycle regulatory proteins such as cyclin E and cyclin-dependent kinase (CDK), play an important role in cell proliferation. In this study, we demonstrate that treatment of HSC with LAEE increases cyclin E expression and cyclin E/CDK2 activity, which may underlie the promitogenic effects of this compound. In addition, LAEE increases ERK and JNK activity, and these pathways play an important role in the activation of AP-1-dependent gene expression by LAEE. The stimulation of intracellular signaling pathways in HSC by this well-characterized ethanol metabolite may contribute to ethanol-induced hepatic fibrogenesis.
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PMID:The ethanol metabolite, linolenic acid ethyl ester, stimulates mitogen-activated protein kinase and cyclin signaling in hepatic stellate cells. 1281 18


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