Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclin-dependent kinases (Cdks) play a key role in orchestrating the coordination of cell cycle progression in proliferating cells. The escape from the proper control of the cell cycle by the upregulation of cyclins or aberrant activation of Cdks leads to malignant transformation. In quiescent cells and/or terminally differentiated cells, the expression pattern and activity of Cdks is altered. In postmitotic neurons, expression of mitotic kinases is downregulated, whereas Cdk5 expression becomes upregulated. Similarly to other Cdks, free Cdk5 displays no enzymatic activity and requires complex formation with a specific regulatory subunit. Two activators of Cdk5 have been identified. p35 and its isoform p39 bind to, and thereby activate, Cdk5. Unlike mitotic kinases, Cdk5 does not require activating phosphorylation within the T-loop. Because p35 is a short-lived protein, the p35/Cdk5 complexes are unstable. The stability of the p35 protein is regulated by its Cdk5-mediated phosphorylation of p35. Activated p35/Cdk5 kinase phosphorylates numerous physiological targets. The proper phosphorylation of the most important substrates, such as tau protein and neurofilament H, is essential for the correct regulation of the cytoskeletal organization, thereby regulating cell adhesion, motility, and synaptic plasticity. Moreover, Cdk5 regulates the activity of the p53 tumor suppressor via phosphorylation. p53 is upregulated in multiple neuronal death paradigms, including hypoxia, ischemia, and excitotoxicity, and plays a key role in the induction of apoptosis. On the other hand, an abnormally high expression and elevated activity of Cdk5 was observed in neurodegenerative diseases, suggesting the application of Cdk inhibitors for their therapy. Considering the action of some Cdk inhibitors on the expression and activity of the p53 protein, their therapeutic efficacy must be carefully evaluated.
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PMID:Interplay between the p53 tumor suppressor protein family and Cdk5: novel therapeutic approaches for the treatment of neurodegenerative diseases using selective Cdk inhibitors. 1700 20

DNA damage is known to be an initiator of neuronal death in neurodegenerative conditions such as Parkinson's and Alzheimer's diseases. The mechanism linking DNA damage and neuronal death is not completely understood. Here, we delineate the mechanism by which neuronal death evoked by DNA damage is controlled. Using mouse cortical neurons and SH-SY5Y human neuroblastoma cells, we identify a critical role of ERK signaling in neuronal death induced by DNA damage upon mitomycin C treatment. In addition, we provide evidence that the ERK signaling regulates Cyclin-dependent kinase 5 (Cdk5) activity and stability of tumor suppressor p53. Mitomycin C increased expression of p35, a specific activator of neuronal Cdk5 in an ERK1/2-dependent manner. Moreover, stability of p53 was increased by its phosphorylation on Ser33 and Ser46 by Cdk5, leading to neuronal death. Finally, we show that activated ERK induced increased expression of the Egr-1 transcription factor, which then bound to the promoter region of p35. We suggest subsequent increase of p35 expression and Cdk5 activity contribute to p53-dependent neuronal death. Thus, the present finding provides a new insight into a molecular mechanism underlying DNA damage-induced neuronal death.
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PMID:Regulation of cyclin-dependent kinase 5 and p53 by ERK1/2 pathway in the DNA damage-induced neuronal death. 1711 79

Cdk5 is an atypical cyclin-dependent kinase localized in the brain, and its activity is dependent upon binding to p35/p39. In addition, while cdk5 has important physiological functions related to brain development, the breakdown of cdk5/p35 into cdk5/p25 increases its kinase activity and neurotoxicity. Interestingly, in recent years increased cdk5/p25 expression has been demonstrated in the brains of patients with Alzheimer's and Parkinson's diseases. Experimental studies performed in neuronal cell cultures indicate that cdk5/p25 plays a prominent role in apoptosis. Moreover, an apoptotic pathway, via an intracellular calcium increase following calpain activation and cdk5/p25 formation, has been postulated. Cdk5/p25 subsequently phosphorylates the nuclear transcription factor myocyte enhancer factor (MEF2), thereby inhibiting its prosurvival activity. However, cdk5/p25 could phosphorylate other substrates such as tau and p53, as well as the retinoblastoma protein pRb. All these data lend credence to the hypothesis that cdk5/p25 acts as a master regulator of neuronal cell death. In addition, cdk5/p25 might also interact with other pathways such as glycogen synthetase kinase 3beta (GSK3beta) and c-JUN kinase. Drugs like roscovitine, flavopiridol, calpain inhibitors, kenpaullone and induribins, which inhibit cdk5/p25 formation, constitute potential drugs for the treatment of neurological disorders. Furthermore, the dual inhibitory effect of some of these drugs on cdk5 and GSK3beta could be beneficial.
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PMID:The role of CDK5/P25 formation/inhibition in neurodegeneration. 1716 Jan 45

Huntingtin is an antiapoptotic protein that becomes toxic when its polyglutamine stretch is expanded, resulting in Huntington's disease (HD). Protein context and posttranslational modifications regulate huntingtin toxicity. Identifying signaling pathways that act on huntingtin is, therefore, key to understanding huntingtin function in normal and pathological conditions. We show here that huntingtin is phosphorylated by the cyclin-dependent kinase 5 (Cdk5) at serines 1181 and 1201. Phosphorylation can be induced by DNA damage in vitro and in vivo. The state of huntingtin phosphorylation is a crucial regulator of neuronal cell death. Absence of phosphorylation of huntingtin at serines 1181 and 1201 confers toxic properties to wild-type huntingtin in a p53-dependent manner in striatal neurons and accelerates neuronal death induced by DNA damage. In contrast, phosphorylation at serines 1181 and 1201 protects against polyQ-induced toxicity. Finally, we show in late stages of HD a sustained DNA damage that is associated with a decrease in Cdk5/p35 levels. We propose that wild-type huntingtin is a component of the DNA damage response signal in neurons and that the Cdk5/DNA damage pathway is dysregulated in HD.
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PMID:Phosphorylation of huntingtin by cyclin-dependent kinase 5 is induced by DNA damage and regulates wild-type and mutant huntingtin toxicity in neurons. 1761 Dec 84

The p53 tumor suppressor protein, a critical modulator of cellular stress responses, is activated through diverse mechanisms that result in its stabilization and transcriptional activation. p53 activity is controlled by transcriptional, translational, and post-translational regulation. The major mechanisms of p53 regulation occur primarily through interactions with HDM2, an E3 ubiquitin ligase that leads to p53 nuclear export and degradation. Here, we demonstrate that hydrogen peroxide-induced oxidative stress elicits down-regulation of HDM2. c-Abl mediates down-regulation of HDM2, leading to an increase of p53 level. Moreover, Cdk5 (cyclin-dependent kinase 5), a proline-directed Ser/Thr kinase, additionally increases p53 stability via post-translational modification of p53 in response to hydrogen peroxide. The p53 protein stabilized by c-Abl and Cdk5 is transcriptionally active; however, transcription of its target gene is differentially regulated with selective binding of p53 on promoter regions of its target genes by c-Abl. In addition, c-Abl modulates Cdk5 activity via phosphorylation of tyrosine 15 in cooperation with cleavage of p35 to p25. Our results show that c-Abl and Cdk5 cooperatively regulate maximal activation of p53, resulting in neuronal death in response to oxidative stress by hydrogen peroxide. These findings aid in clarifying the mechanism underlying the occurrence of neuronal apoptosis as a result of c-Abl and Cdk5-mediated p53 stabilization and transcriptional activation.
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PMID:Cooperative roles of c-Abl and Cdk5 in regulation of p53 in response to oxidative stress. 1849 Apr 54

Scotin is a pro-apoptotic mammalian gene, which is induced upon DNA damage or cellular stress in a p53-dependent manner. In this report, we have used Drosophila as a model system to obtain a preliminary insight into the molecular mechanism of Scotin function, which was further validated using the mammalian system. Targeted expression of Scotin in developing Drosophila induced apoptosis and developmental defects in wings and eyes. Co-expression of Scotin with the anti-apoptotic protein p35, while inhibited the apoptosis in both dividing and non-dividing cells, rescued adult wing or eye phenotypes only when Scotin was expressed in non-dividing cells. This suggests that mechanisms of Scotin-induced apoptosis in dividing and non-dividing cells may vary. Suppressor-enhancer screen using cell cycle regulators suggested that Scotin may mediate cell cycle arrest at both G(1)/S and G(2)/M phases. Overexpression of Scotin in mammalian cells resulted in mitotic arrest and subsequently apoptosis. Furthermore, a larger proportion of cells overexpressing Scotin showed sequestration of Cyclin B1 in the cytoplasm. These results suggest that one of the ways by which Scotin induces apoptosis is by causing cell cycle arrest.
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PMID:Cell cycle regulation by the pro-apoptotic gene Scotin. 1867 3

Inflammatory cytokines, produced mainly by activated microglia in the brain, can enhance neuronal degeneration and the amyloid-beta-plaque production involved in Alzheimer's disease (AD). We previously demonstrated that the expression of the pro-inflammatory cytokine interleukin-18 (IL-18) colocalizes with plaques and hyperphoshorylated tau containing neurons in AD patients. Here we exposed neuron-like, differentiated SH-SY5Y neuroblastomas to IL-18 and observed that the protein levels of p35, Cdk5, GSK-3beta, and Ser15-phosphorylated p53 increased during 6 h-24 h. Tau phosphorylation and expression of cyclin G1, involved in neuronal regeneration, increased at 72 h. In vivo, over-expression of IL-18 may induce hyperphosphorylation of tau and induce cell cycle activators.
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PMID:Interleukin-18 increases expression of kinases involved in tau phosphorylation in SH-SY5Y neuroblastoma cells. 1894 85

Inactivation of tumor suppressor p53 results in loss of the apoptosis-regulating function of the p53 protein in tumor cells. Restoration of wild-type p53 expression in p53 mutant tumor cells increases tumor susceptibility to CTL-mediated cytolysis. However, the direct role of p53 in regulating tumor sensitivity to NK cell-mediated lysis and the functional relationship between p53 and granzymes in the control of tumor killing are still poorly documented. In this study, we found that p53 can sensitize tumor-killing susceptibility to NK and granzyme K-mediated cytolysis. Granzyme K is constitutively expressed in high levels in NK cells and induces rapid caspase-independent cell death. Granzyme K may exert a critical role in NK cell-mediated tumor clearance. p53 associates with granzyme K and is a physiological substrate of granzyme K. p53 was processed to three cleavage products of p40, p35, and p13 fragments at Lys(24) and Lys(305). These three cleavage products harbor strong proapoptotic activities that amplify the proapoptotic action of p53 to potentiate tumor-killing sensitivity. Therefore, p53 is as a cytotoxic bomb that can be triggered by granzyme K, leading to potentiating killing efficacy.
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PMID:Ignition of p53 bomb sensitizes tumor cells to granzyme K-mediated cytolysis. 1920 68

Conditional expression of transgenes in Drosophila was produced using the Geneswitch system, wherein feeding the drug RU486/Mifepristone activates the artificial transcription factor Geneswitch. Geneswitch was expressed using the Actin5C promoter and this was found to yield conditional, tissue-general expression of a target transgene (UAS-GFP) in both larvae and adult flies. Nervous system-specific (Elav-GS) and fat body-specific Geneswitch drivers were also characterized using UAS-GFP. Fourteen genes implicated in growth, apoptosis and senescence regulatory pathways were over-expressed in adult flies or during larval development, and assayed for effects on adult fly life span. Over-expression of a dominant p53 allele (p53-259H) in adult flies using the ubiquitous driver produced increased life span in females but not males, consistent with previous studies. Both wingless and Ras activated form transgenes were lethal when expressed in larvae, and reduced life span when expressed in adults, consistent with results from other model systems indicating that the wingless and Ras pathways can promote senescence. Over-expression of the caspase inhibitor baculovirus p35 during larval development reduced the mean life span of male and female adults, and also produced a subset of females with increased life span. These experiments suggest that baculovirus p35 and the wingless and Ras pathways can have sex-specific and developmental stage-specific effects on adult Drosophila life span, and these reagents should be useful for the further analysis of the role of these conserved pathways in aging.
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PMID:A screen of apoptosis and senescence regulatory genes for life span effects when over-expressed in Drosophila. 2015 9

In Drosophila, the checkpoint protein-2 kinase (DmChk2) and its downstream effector protein, Dmp53, are required for DNA damage-mediated cell cycle arrest, DNA repair and apoptosis. In this study we focus on understanding the function of these two apoptosis inducing factors during ovarian development. We found that expression of Dmp53, but not DmChk2, led to loss of ovarian stem cells. We demonstrate that expression of DmChk2, but not Dmp53, induced mid-oogenesis cell death. DmChk2 induced cell death was not suppressed by Dmp53 mutant, revealing for the first time that in Drosophila, over-expression of DmChk2 can induce cell death which is independent of Dmp53. We found that over-expression of caspase inhibitors such as DIAP1, p35 and p49 did not suppress DmChk2- and Dmp53-induced cell death. Thus, our study reveals stage-specific effects of Dmp53 and DmChk2 in oogenesis. Moreover, our results demonstrate that although DmChk2 and Dmp53 affect different stages of ovarian development, loss of ovarian stem cells by p53 expression and mid-oogenesis cell death induced by DmChk2 do not require caspase activity.
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PMID:Drosophila Chk2 and p53 proteins induce stage-specific cell death independently during oogenesis. 2083 98


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